4, 6-pregnadieno-[3, 2-c] pyrazoles and processes of preparing them



United States Patent 1 Claim. (Cl. 260--239.5)

This invention is concerned generally with novel 4,6- pregn'adieno-[3,2-c]pyrazole compounds, and with processes of preparing the same. More partioularly,it relates to novel 21-hydroxy-, 21-acyloxy-, 21-desoxy-, and '21 fiuoro-l7whydroxy 20 0x0 4,6 pregnadieno-[3,2-c] pyrazole compounds and to processes of preparing these compounds starting from the corresponding 17a,2l-di hydroxy-4,6-pregnadiene-3,20-dione.

This application is a division of co-pending application Serial No. 156,478, filed December 1, 1961, now US. Patent No. 3,067,194, which application is, in turn, a continuation-in-part of application Serial No. 67,172, filed November 4, 1960, now abandoned.

These novel 4,6-pregnadieno-[3,2-c]pyrazole compounds, subject of the present invention, may be chemically represented by structures A and B:

wherein R is fi-rhalogen, j8-hydroxy or keto, but fl-halogen is present at R only when X is halogen, R is fluoro, hydrogen or methyl, R is hydrogen, a-methyl, ,B-methyl or methylene, R is hydrogen, hydroxy, acyloxy or fluoro, R is hydrogen, alkyl, cycloalkyl, arralkyl, aryl or acyl and X is hydrogen or halogen, and wherein any acyl group present as an acyloxy group at R may be the same or different from any acyl group present at R N-substituted-pyrazole compounds having structure A are herein designated as the 1-substituted-4,6-pregnadieno-[3,2-c] pyrazoles, and N-substituted-pyrazole compounds having 3,300,483 Patented Jan. 24, 1967 structure B are designated as the 2'-substituted-4,6-pregnadieno-[3,2-c1pyrazoles.

The above defined 4,6-pregnadien0-[3,2-c]pyrazoles produced in accordance with the present invention possess high anti-inflammatory activity, and are especially effective for the treatment of arthritis and related diseases since they can be administered for their cortisone-like action in low dosage thereby minimizing undesirable side effects.

In preparing our novel chemical compounds, the starting material utilized is a 17u,21-dihydroxy-4,6-pregn adiene-3,2 0-dione which may be identified by the following structural formula:

CHzOH wherein R is fi-hydroxy or p-halogen, but fl-halogen is present at R only when X is halogen, R is hydrogen, fluoro or methyl, R is hydrogen, a-methyl, fl-methyl or methylene, and X is hydrogen or halogen. However, it is clear to those skilled in the art that other starting materials may be similarly converted to the desired end products.

Among the compounds which may be used as a starting material in the process of our invention are:

1 1p,17a,2l-trihydroxy-4,6-pregnadiene-3,20-dione,

1 lfl,1704,2l-trihydroxy-l6a-methyl-4,6-pregnadiene- 3,20-dione,

1 l5, 17a,2 l-trihydroxy-l 6,8-methyl-4,6-pregnadiene- 3,20-dione,

1 1,8, 1 711,2 1 -trihydroxy-1 6-methylene-4,6-pregnadiene- 3,20-dione,

1 1 5, l7a,21-trihydroxy-6-methyl-4,6-pregnadiene- 3,20-dione,

1 1/3,17a,21-trihydroxy-6,16a-dimethyl-4,6-pregnadiene- 3,20-dione,

1 1(3,l7a,21-trihydroxy-6,16fl-dimethyl-4,6-pregnadiene- 3,20-dione,

l 1B,17a,21-trihydroxy-6-methyl-l6-methylene-4,6-

pregnadiene-3,20-dione,

6-fiuoro-1lfl,17u,21-trihydroxy-4,6-pregnadiene-3,20-

dione,

6-fluoro-1 1,8,17a,21-trihydroxy-16a-methyl-4,6-pregnadiene-3,2 0-dione,

6-fluoro-1 15, 17a,21-trihydroXy-16B-methyl-4,6-pregnadiene-3,20-dione,

6-fluoro-11/3,1711,2l-trihydroxy-16-methylene-4,6-

pregnadiene-3 ,20-dione,

9a-fluoro-1 1B,170:,21-trihydroxy-4,6-pregnadiene- 3,20-dione,

9a-fluoro-115,17a,21-trihydroxy-16a-methyl-4,6-

pregnadiene-3,20-dione,

9a-fluoro-l l 8,17u,21-trihydroxy-16B-methyl-4,6-

pregnadiene-3 ,ZO-dione,

9u-fluoro-1 1 8,17u,2l-trihydroxy-16-methylene-4,6-

pregnadiene-3,20-dione,

900-ch1oro-11B,1700,21-trihydroxy-4,6-pregnadiene- 3,2-dione,

900-chloro-115,1700,21-trihydroxy-1600-methyl-4,6-

pregnadiene-3,20-dione,

900-chloro-11p,1700,21-tri hydroxy-16B-methyl-4,6-

pregnadiene-3 ,20-dione,

900-chl0ro-1 15,1700,21-trihydroxy-16-methy1ene-4,6-

pregnadiene-3 ,20-dione,

900-fluoro-1 1fi,1700,21-trihydroxy-6-methyl-4,6-pregnadiene-3,2 O-dione,

9o0-fiuoro-11,8,l700,21-trihydroxy-6,1600-dimethyl-4,6

pregnadiene-3,20-dione,

900-fluoro-1 15,1700,21-trihydroxy-6,16;3-di methyl-4,6-

pregnadiene-3,20-dione,

900-fluoro-11,8,1700,21-trihydroxy-6-methyl-16-methylene- 4,6-pregnadiene-3 ,20-dione,

900-chloro-1 1B,1700,21-trihydroxy-6-methyl-4,6-pregnadiene-3,20-dione,

900-011101'0-1 1fi,1700,21-trihydroxy-6,1600-dimethyl-4,6-

pregnadiene-3,20-dione,

900-chloro-1 1B,1700,21-tri hydroxy-6,16fi-dimethyl-4,6-

pregnadiene-3 ,ZO-dione,

900-chloro-1 1B,1700,21-trihydroxy-6-methyl-16-1nethylene- 4,6-pregnadiene-3,20-dione,

900-chloro-1 1B,1700,21-trihydroxy-6-fluoro-4,6-pregnadiene-3,20-dione,

6,900-difluoro-1 15,1700,21-trihydroxy-4,6-pregnadiene- 3,20-dione,

6,900-difiuoro-l 1,B,1700,2 l-trihydroxy-l 600-methyl-4,6-

pregnadiene-3,20-dione,

6,900-difiuoro-1 1B,1700,21-trihydroxy-16fi-methyl-4,6-

pregnadiene-3 ,ZO-dione,

6,900-difluoro-1 15,1700,21-trihydroxy-16-methylene-4,6-

pregnadiene-3,20-di0ne,

900-chloro6-fiuoro-1 1p,1700,21-trihydroxy-4,6-pregnadiene-3,20-dione,

900-ohloro-6-fl uoro-1 1p,1700,21-trihydroxy-1600-methyl- 4,6-pregnadiene-3,ZO-dione,

900-ch1oro-6-fluoro-1 1/3,1700,21-trihydroxy-16B-methyl- 4,6-pregnadiene-3,20-dione,

900-chl0ro-6-fluoro-1 1,8,1700,21-trihydr0xy-16-methylene- 4,6-pregnadiene-3,20-dione,

and the ll-keto-analogues of the above compounds;

900,1 lfl-dichloro-1700,21-dihydroxy-4,G-pregnadiene- 3,20-dione,

900,1 lfi-dichloro-1700,21-dihydroxy-1600-methy1-4,6-

pregnadiene-3,20-dione,

900,1 1fi-dichloro-1700,2l-dihydroxy-16/3-methyl-4,6-

pregnadiene-3,20-dione,

900,1 1,6-dich1or0-1700,21-dihydroxy-16-methylene-4,6-

pregnadiene-3,20-dione,

900,11,8-dichloro-6-fluoro-1700,21-dihydroxy-4,6-pregnadiene-3,20-dione,

900,11B-dichloro-6-fluoro-1700,21-dihydroxy-1600-methyl- 4, fi-pregnadiene-3,20-dione,

900,1 1B-dichloro-6-fluoro-1700,21-dihydr0xy-16B-methyl- 4,6-pregnadiene-3,20-dione,

900,1 1,8-dichlor0-6-fluoro-1700,21-dihydroxy-16- methylene-4,6-pregnadiene-3 ,20-dione,

900,11fi-dichloro-1700,21-dihydroxy-6-methyl-4,6-

pregnadiene-3,20-dione,

900,11,8-dich1oro-1700,21-dihydroxy-6,1600-dimethyl- 4,6-pregnadiene-3 ,ZO-dione,

900,1 -dichloro-1700,21-dihydroxy-6,16/i-dimethyl- 4,6-preg-nadiene-3,20-dione,

900,1 1fl-dichloro-1700,2 l-dihydroxy-6-methyl-l6- methylene-4,6-pregnadiene-3 ,20-dione,

900-bromo-1lfi-ohloro-1700,21-dihydroxy-4,6-pregnadiene-3,20-dione,

900-bromo-1 1fi-chloro-1700,21-dihydroxy-1600-methyl- 4,6-pregnadiene-3,20-dione,

900-bromo-1lfl-chloro-1700,21-dihydroxy-16fi-methyl- 4,6-pregnadiene-3,20-dione,

900-bromo-1 1 8-chloro-170:0,21-dihydroxy-16-methylene- 4,6-pregnadiene-3,20-dione,

900-'bromo-1 1 B-chloro-1700,2l-dihydroxy-6-fluoro-4,6-

pregnadiene-3,20-dione,

900-bromo-11B-chloro-1700,21-dihydroxy-6-fluoro-1600- methyl-4,6-pregnadiene-3,20-dione,

900-bromo-1 1fl-chloro-1700,21-dihydroxy-6-fluor0-16fimethyl-4,6-pregnadiene-3,ZO-dione,

900-bromo-1 1 8-chloro-1700,21-dihydr0xy-6-fluoro-16- methylene-4,6-pregnadiene-3,20-dione,

900-bromo-1 lfi-ohloro-1700,21-dihydroxy-6-methyl-4,6-

pregnadiene-3,20-dione,

900-bromo-1lfl-chloro-1700,21-dihydroxy-6,1600-dimethyl- 4,6-pregnadiene-3,20-dione,

900-bromo-1 1fi-c-hloro-1700,21-dihydroxy-6,16fl-dirnethyl- 4,6-pregnadiene-3,20-dione,

900-bromo-1 l18-ehl0r0-1700,21-dihydroxy-6-methyl-l6- methylene-4,6-pregnadiene-3,20-dione and the like.

The above named starting materials for our invention can be prepared by the introduction of the various substituents, namely the l6o0-methyl-, 16 3-methyl-, 16-methylene-, 600-methy1-, 600-fluoro-, 900-fluoro or the 900-chloro groups into a 1700,21-dihydroxy-4-pregnene-3,2O-dione according to known procedures capable of general application. More than one substituent may the introduced into the unsubstituted steroid in any order, although it is generally preferred to introduce a 900-ha1ogen substituent l-ast.

An 11,8,1700,21-trihydroxy-4-pregnene-3,20-di0ne compound may be converted into the correspondingly substituted 900,llfl-diohloroor the 900-bromo--chloro- 1700,21-dihydroxy 4 pregnene-3,20-dione compound by first dehydrating the 11,8,1700,21-trihydroxy-4-pregnene- 3,20-dione at the 9(11)-position to form the corresponding 9(11)-pregnene, then acetylating at the 21-position, and finally halogenating at the 900,11B-positions, for example, following the detailed procedures given in Example 5.

All of the above 1700,21-dihydroxy-4-pre.gnene-3,20- dione compounds may be converted into the corresponding 1700,21-dihydr0xy 4,6 pregnadiene-3,20-dione compounds by chloranil dehydrogenation, preferably of the 21-ester, in order to prevent extensive degradation of the dihydroxyacetone side chain, for example, following the detailed procedure in Example 5, which is of general application. Alternately, chloranil dehydrogenation takes place as an intermediate step in the preparation of the desired starting material.

It has been found that the starting materials defined above will react with aqueous formaldehyde solutions in the presence of strong acid to form compounds having the formula:

wherein R is [3-hydroxy or S-halogen but fl-halogen is present at R only when X is halogen, and R R and X have the significance a bove defined. For example, cold, concentrated HCl and formalin are added to a stirred suspension of the steroid in chloroform, cooled to about 0 C. The mixture is then allowed to come to room temperature and stirred for several hours to afford the corresponding 1700,20,20,21 bis(methylenedioxy)-derivative.

In a preferred embodiment of'ourinvention, the 17st, 20,20,21 bis(methylenedioxy) 4,6 pregnadiene 3,11- dione compound which has the following formula:

wherein R R and X have the significance above defined, is prepared by oxidation of the corresponding 11fi-hydroxy-17a,20,20,21 bis(methylenedioxy) 4,6- pregnadiene-3-one, for example, with chromium trioxide in a non-aqueous base such as pyridine. If desired, however, the 17a,20,20,2l-bis(methylenedioxy)4,6-pregnadiene-3,11-dione maybe prepared directly by the reaction of the 17u,21-dihydroxy-4,6-pregnadiene-3,l1,20-trione with formaldehyde solution in the presence of an acid as described in the preceding step.

Upon treatment of an llfi-hydroxy-, llfl-halogem, or 1l-keto-17a,20,20,21-bis(methylenedioxy)-4,6 pregnadiene-S-one compound with an alkyl formate and sodium hydride in an inert atmosphere there is formed the cor responding 17u-20,20,21-bis(rnethylenedioxy) 2 hydroxymethylene-4,6-pregnadieue-3-one which has the following structure:

wherein R is B-halogen, B-hydroxy and/ or fi-formyloxy-, or keto-, but fi-halogen is present at R only when X is halogen, and R R and X have the significance above defined. In a preferred embodiment of our invention, the steroid is dissolved in a solvent such as benzene and the resulting solution is cooled to room temperature and treated with ethyl formate. The air in the system is replaced with nitrogen, sodium hydride is added and the mixture is stirred at room temperature for several hours.

The 17a,20,20,21-bi8 (methylenedioxy) -2-hydroxymethylene-4,6-pregnadiene-3-one compound reacts with hydrazine in an inert atmosphere to form the corresponding 17oz,20,20,21-bis(methylenedioxy)-4,6-pregnadieno [3, 2-clpyrazole.

Upon treatment of a 17d,20,20,21-bis(methylenedioxy)-2-hydroxymethylene-4,6-pregnadiene-3-one compound with a lower alkanol in the presence of an acidic reagent such a p-toluenesulfonic acid the corresponding 17a,20,20,21-bis(methylenedioxy)-2-alkoxymethylene 4, 6-pregnadiene-3-one is formed. When the latter compound is reacted with -a monosubstituted hydrazine, the corresponding N-substituted-4,6 pregnadieno [3,2-c] pyrazole compounds are formed. The N-substituted-4,6- pregnadieno-[3,2-c1pyrazoles having structure A are designated as the 1'-substituted-4,6-pregnadieno-[3,2-c] pyrazoles, and the N-substituted-pyrazole compounds having structure B are designated as the 2-substituted-4,6- pregnadieno-[3,2-c1pyrazoles.

dioxy) -2-hydroxymethylene-4,6-pregnadiene-B-one wherein R R R and X have the significance above defined, and wherein R is an alkyl, cycloalkyl, aralkyl or an aryl group. The products formed may be separated by chromatography.

Upon treatment of a l7a,20,20,21-bis(methylenecompound directly with a monosubstituted arylhydrazine, without the intermediate formation of the 2-alkoxymethylcue-derivative, one isomer is generally formed in preponderant amounts, whereas when reacting the 17a-20, 20,2l-bis(methylenedioxy)-2-alkoxymethylene-4,6 pregnadiene-3-one compound with a monosubstituted arylhydrazine, significant amounts of both isomers are obtained. When these reactions take place with monosubstituted alkylhydrazines, mixtures may be obtained when starting with the 2-hydroxymethylene-steroid as well as with the 2-alkoxymethylene-steroid. A mixture of isomers may also result from the reaction of a monosubstituted hydrazine with a 2-hydroxymethylene-compound which possibly contains variable amounts of the 2-alkoxymethylenederivative due to the operating procedures employed, for example, due to recrystallization in the presence of a trace of alcohol a solution of the 2-hydroxymethylene-compound from which acid has not been completely removed.

Among the monosubstituted hydrazines which may be used for the process of our invention are: alkylhydrazines, such as methylhydrazine, ethylhydrazine, propylhydrazines, butylhydr'azines, fl-hydroxyethylhydrazine, cycloalkylhydrazines; arylhydrazines including phenylhydrazine and the substituted phenylhydrazines, such as o-, m-, and p-halophenylhydrazines, 0-, m-, and p-tolylhydrazines, o-, m-, and p-alkoxyphenylhydrazines, o-, m-, and pnitrophenylhydrazines, l-hydrazinonaphthalene, Z-hydrazinopyridine, 3-hydrazinopyridine, 4-hydrazinopyridine, 4-hydrazinopyridine oxide, and Z-hydrazinopyrimidine; aralkylhydrazines, such as benzylhydrazine and phenylethylenehydrazine.

7 dy1)-, N-(4"-pyridyloxide)-, N-(2"-pyrimidyl)-; N-aralkyl-, such as N-benzyland N-phenylethenyl-4,G-pregnadieno- [3 ,Z-c] pyrazoles.

The N-alkyl 4,6 pregnadieno-[3,2-c] pyrazoles may also be prepared by direct alkylation of the N-unsubstituted 4,6 pregnadieno [3,2-c]pyrazoles.

A 17a,20,20,21-bis(methylenedioxy) 11B byclroxy- 4,6-pregnadieno-[3,2-c] pyrazole which has a 9a-halosubstituent is preferably prepared by the following alternate route. Using the procedures described above, the 90c ha'lo 11B,l7oc,21 trihydroxy 4,6 pregnadiene- 3,20-dine is converted into the corresponding 1711,2020, 21-bis(methy-lenedioxy) 9a halo 11B hydroxy-4,6- pregnadiene-3-one. The latter compound is then oxidized to the 17a,20,20,2l-bis(methylenedioxy) 9a halo 4,6- pregnadiene-lll-dione, which is reacted with ethyl formate and sodium hydride to form the 2-hydroxymethylene-derivative. The latter compound is reacted with hydrazine, or a mono-substituted hydrazine, to give the corresponding 170:,20,20,21bi5 (methylenedioxy) 90c haloll-oxo-4,6-pregnadieno-[3,2-c]pyrazole compound, or the N-substituted derivative thereof. The latter compound is then reduced to the corresponding 17a,20,20,21-bis (methylenedioxy)-9u-halo-l1B-hydroxy-4,6 pregnadieno- [3,2-c]pyrazole compound, for example, by adding a saturated solution of sodium :borohydride to a solution of the steroid in a mixture of triethylamine and isopropyl alcohol to which we prefer to add a little water, and allowing the mixture to stand overnight.

The N-unsubstituted 17a,20,20,21 bis(rnethylenedioxy) 4,6 pregnadieno-[3,2-c]pyrazole compounds are converted into N-acyl-derivatives having the following structures:

L- QM,

wherein R is B-h'alogen, ,B-hydroxy or keto, but p-h-alogen is present at R only when X is halogen; R R and X have the meaning described above; and wherein R is an acyl group, by treating with an acylating agent, e.g., a lower hydrocarbon carboxylic acid acylating agent such as benzoic anhydride or tertiary butyl acetyl chloride; at lower alkanoic anhydride or lower alkanoyl halide such as acetic anhydride, propionic anhydride or acetyl chloride; or a polybasic anhydride such as 8,3-dimethylglutaric anhydride, succinic anhyd-ride and the like, in the presence of an organic base such as pyridine.

Upon treatment of any of the above described 17,20, 20,2-1-bis(methylenedioxy) 4,6 pregnadieno [3,2-c]

CHzORi "'0 II Bit-p: lmv R3 wherein R is ti-halogen, 8-hydroxy or keto, but B-halogen is present at R only when X is halogen; R R and X have the meaning described above; and wherein R is acyl, alkyl, cycloalkyl, aryl or aralkyl and R is hydrogen, an acyl group corresponding to the organic acid used in this reaction, or a mixture of the two.

Any 'acyl groups present at R; and/or at R may be removed by treating the steroid with sodium methoxide in methanol at room temperature to form the corresponding 17a,21-dihydroxy 20 oxo 4,6 pregnadieno-[3,2- c]pyrazole. Acyl groups present at the R position may be selectively removed by treatment with aqueous acetic acid.

The compounds of our invention include, among others, the following:

1 1 8, 17a,21-trihydroxy-20-oxo-4,6-pregnadieno- [3,2-c]

pyrazole,

1 1fi,17 x,21-trihydroxy-16a-methyl-20-oxo4,6-pregnadienO- 3,2-c] pyrazole,

1 1,8,17u,21-trihydroxy-16,18-methyl-20-oxo-4,6-pregnadieno- 3,2-c] pyrazole,

1 1B,17a,2l-trihydroxy-16-methylene-20-oxo-4,6-pregn adieno- 3,2-c] pyrazole,

1 1 B, 17a,2 1-trihydroxy-6-methyl-20 -oxo-4,6-pregnadieno- [3,2-c] pyrazole,

1 1B,17a,21-trihydroxy-6,16u-dimethyl-20-oxo-4,6-pregnadieno- 3,2-0] pyrazole,

1 1,8,l7u,21-trihydroxy-6,16fi-dimethyl-20 oxo-4,6-pregnadieno- 3,2-c] pyrazole,

1 1,8,1706,21-trihydroxy-6-methyl-16-methylene-20-oxo- 4,6 pregnadieno- 3 ,2-'c] pyrazole,

6-fluoro-1 1/3,17a,21-trihydroxy-20-oxo-4,6-pregnadieno- [3 ,2-c] pyrazole,

6-fluoro 11,8-1711,21-trihydroxy-16/3-met-hyl-20-oXo-4,6-

pregnadieno-[ 3 ,2-c] pyrazole,

6-fiuoro-1 1H,17a,21-trihydroxy-16-methylene-20-oxo-4,6-

pregnadieno- 3,2-c] pyrazole,

t-flUOI'O-1 1,3,17a,21-trihydroxy-20-oxo-4,6-pregnadieno- [3,2-c] pyrazole,

- 9u-chloro-11B,17a,21-trihydroxy-20-oxo-4,6-pregnadieno- [3,2-c1pyrazole,

9a-chloro-1 1B,17u,21-trihydroxy-16B-methyl-20-oXo-4,6-

pregnadieno- 3,2-c] pyrazole,

9oc-Ch1OIO-1 1B,17u,21-trihydroxy-16-methylene-20-oxo- 4,6-pregnadieno- [3 ,2-c] pyrazole,

9a-fluoro-1 1 B, 17a,2 1-trihydroxy-6-methyl-20-oxo-4,6-

pregnadieno- [3,2-c1pyrazole,

9a-fluoro-1 1 B, 17a,21 -trihydroxy-6;1 6u-dimethyl-20-oxo- 4,6-pregnadieno- [3 ,2-c] pyrazole,

9u-fluoro-1 1B,17a,21-trihydroxy-6,16B-dimethy1-20-oxo- 4,6-pregnadieno-[3,2-c1pyrazole,

9a-fluoro 1 1B,17a,2-1-trihydroxy-6-methyl-16-methylene- 20-oxo-4,6-pregnadieno- 3,2-c] pyrazole,

9a-chlor0-1 1B,17a,21-trihydroxy-6-methyl-20-oxo-4,6-

pregnadieno- 3 ,2-c] pyrazole,

9a-ch1oro-11B,17a,21-trihydroXy-6,l6a-dimethyl-20-oxo- 4,6-pregnadieno- 3,2-c1pyrazole,

9a-chloro-1 1B,17a,21-trihydroxy-6,16B-dimethyl-20-oxo- 4,6-pregnadieno- 3,2 c] pyrazole,

9u-Ch101'0-1 1B,17u,21-trihydroxy-6-methyl-16-methy1ene- 20oxo-4,6-pregnadieno- 3,2-c]pyrazo1e,

9a-chloro-6-fiuoro-11B,17a,21-trihydroxy-20-ox0-4,6-

pregnadieno- [3 ,2-c]pyrazole,

9ot-chloro-6-fluoro-1-1B,17u,21-trihydroXy-16a-methy1-20- oXo-4,6-pregnadieno- [3 ,2-c1pyrazole,

9u-chloro-6-fiuoro-1 1B,17a,21 trihydroxy-16-rnethy1ene- 20-oxo-4,6pregnadieno- 3 ,2-c] pyrazole,

6,9a-difluoro-11B,17a,21-trihydroxy-ZO-oxo4,6-pregnadieno- [3,2-c1pyrazole,

6,9a-difluoro- 1-1 B, 1 7a,2 1 trihydroXy-1 6-methylene-20- oxo-4,6-pregnadieno- [3,2-c1pyrazole,

and the 11-oxo-ana-logues of all of the above compounds, the

9 oc,1 1 B-dichloro-17tx,2 1 -dihydroxy-20-oX0-4,6-pregnadieno- 3 ,2-c]pyrazo1e, 4

900,1 lB-dichloro-17u,21-dihydroXy- 16a-methyl-2O-0x0-4,6-

pregnadieno- 3,2-c]pyrazole,

9u,11B dich10ro 17u,21-dihydroXy-16-methylene-20-oxo- 4,6-pregnadieno- 3,2-c] pyrazole,

9:1,1 1B-dichloro-6-fluoro-17a,21-dihydroXy-20-oXo-4,6-

pregnadieno- 3,2-c] pyrazole,

911,1 1B-dichloro-6-fluoro-170:,2 l-dihydroxy-l 6a-Inethyl-20- oxo-4,6-pregna dieno- 3,2-c] pyrazole,

90:,1 1B-dichloro-6-flu-oro-17a,2l-dihydroxy-l6B-methyl-20- oxo-4,6-pregnadieno- 3,2-c] pyrazole,

90:,11B-dichloro-6-fluoro-17a,21-dihydroxy-16-methy1ene- 20-oxo-4,6-pregnadieno- [3 ,2-c] pyrazole,

90:,1 1B-dichloro-1711,21-dihydroXy-6-methyl20-oxo-4,6-

pregnadieno- 3 ,2-c] pyrazole,

9on1 1B-dichloro-17a,21-dihydroxy-6,1 6u-dimethy-l-20-oxo- 4,6-pregnadieno- 3 ,2-c] pyrazole,

9a,11B-dichloro-17u,21-dihydroXy-6,16B-dimethyl-20-oxo- 4,6-pregnadieno- [3 ,2-c] pyrazole,

9a,1 1 B-dichloro- 1 7oc,2 1-dihydroXy-6-1nethyl4 6-methylene- 20-oxo-4,6-pregnadieno- 3,2-c] pyrazole,

nadieno-[3,2-c]pyrazole,

9u-bromo-1 1B-chloro-17a,21-dihydroxy-16a-methy1-20- oxo-4,6-pregnadien0-[3,2-c]pyrazo1e,

9u-bromo-1 lB-chloro-17u,21-dihydroxy-16B-methy1-20 oxo-4,6-pregna dieno- 3,2-c] pyrazole,

9u-brorno-1 1B-chloro-17oc,21-dihydroxy-16-methylene-20- oxo-4,6-pregnadieno- 3,2-c] pyrazole,

9a-bromo-1 1Bchloro-6-fluoro-17a,21-dihydroxy-20-oxo- 4,6-pregnadieno- [3 ,2-c] pyrazole,

9a-bromo- 1'1B-chloro-6-fluoro-17a,21-dihydroxy-16- methylene-20-oxo-4,6-pregnadieno- [3 ,2-c] pyrazole,

9a-bromo-l lB-chloro- 1 7oc,2 1-d1hYdIOXY-G-IIICthYl-ZO-OXO- 4,6-pregnadieno- 3 ,2-c] pyrazole,

9a-brorno-1 1B- chloro-17a,21-dihydroXy-6,16a-dimethyl- 20-oxo-4,6-pregnadieno- 3 ,2-c] pyrazole,

9a-bromo l lB-chloro-17a,21-dihy-droXy-6,16B-dimethyl- 20-oxo-4,6-pregnadieno- 3,2-c]pyrazo1e,

and 9a-bromo-1 1B-chloro-170,21-dihydroxy-6-methyl-16- methylene-ZO-oxo-4,6-pregnadieno-[3,2-c] pyrazole as well as the 1- and 2-alkyl-, the 1- and 2'-cycloalkyl-, the 1'- and 2'-aryl-, and the 1'- and 2'-aralky1-derivatives of all of the above named compounds.

The N-acyl-derivatives of the above described 170:,21- dihydroxy-ZO-oxo 4,6 pregnadieno-[3,2-c]pyrazoles are preferably obtained 'by treating the corresponding N-acyl- 17a,20,20,21 bis(methylenedioxy) 4,6 pregnadieno- [3,2-c]pyrazole compound with a dilute organic acid to remove the 17a,2'(),20,21-bis(methylenedioxy)protecting group.

The 21-acyl derivatives of the above described 1701,21- dihydroxy 20 OX0 4,6-pregnadieno-[3,2-c]pynazoles in which R is H may be prepared by heating an N-acyl- 17a,21-dihydnoxy-20 0X0 4,6-pregnadien0-[3,2-c]pyrazole 21-acylate with aqueous acetic acid, whereupon the N-acyl-group is selectively removed.

The N-acyl-Zl-acylate derivatives of the above described 17a,21-dihydroxy-ZO-oxo-4,6-pregnadieno-[3,2-c] pyrazoles in which both acyl groups are the same may be prepared (1) by reacting a 17a,21-dihydroxy-20-oXo-4,6-

pregnadieno-['3,2 c]pyrazole with two equivalents of an acylating agent or (2) by reaction of an N-acyl-17a,21- dihydroxy-20-oxo 4,6 pregnadieno- [3,2-c]pyrazole with one equivalent of an iacylating agent in which the acyl group of the acylating agent is the same as the acyl group already present at the N-position of the pyrazole.

The N-acyl-Zl-acylate derivatives of the above described 17a,21-dihydroxy 20 0X0 4,6 pregnadieno- [3,2-c1pyrazoles in which the acyl groups are different are prepared by reaction of an N-acyl-17a,21-dihydroxy- 20-oXo-4,6-pregnadieno-[3,2-c]pyrazole with an acylating agent in which the acyl group of the acylating agent is different from the acyl group already present at the N- position of the pyrazole.

Acylating agents which can be used for this purpose include a lower hydrocarbon carboxylic acid acylating agent such as benzoic anhydride, tertiary butyl acetyl chloride; a lower alkanoic anhydride or lower alkanoyl halide such as acetic anhydride, propionic anhydride; or a polybasic anhydride such as B,B-dirnethyl-glutaric anhydride, succinic anhydride and the like, in the presence of an organic base such as pyridine.

The 1711,21-dihydroxy-20-oxo-4,G-pregnadieno-[3,2-c] pyrazole is reacted with methane sulfonyl chloride in a non-aqueous base to form the 21-mesylate. A steroid in which R is hydrogen is preferably converted to the N- acyl derivative before undergoing this reaction.

The ;,21-dihydr-oxy-20-oxo-4,6-pregnadieno-[3,2-c] pyrazole 21-mesylate is heated with an alkali iodide to form the 21-iodo-compound. In a preferred method for carrying out this reaction, sodium iodide is added to the heated at reflux temperature for approximately one hour.

9a-bromo-1 1.,8-chloro-6-fiuoro-17u-hydroxy-16-methylene- 20-oxo-4,6 preg'nadieno-[3,2-c1pyrazole,

9a-brorno-1 1.5-chloro-17a-hydroxy-6-methyl-20-oxo-4,6-

pregnadieno-[3,2-c]pyrazole,

9a-bromo-l1fl-chloro-17u-hydroxy-6,16a-dimethyl-20- oxo-4,6-pregnadieno-[3,2-c]pyrazole,

9a-bromo-1 lfl-chloro-17ot-hydroxy-6,16p-dirnethyl-20- oxo-4,6-pregnadieno-[3,2c]pyrazole,

9a-bromo-1 lfl-chloro-17ot-hydroxy-6-methyl-16-methylene-20-oxo-4,6 pregnadieno-[3,2-c]pyrazole,

as well as the 1'- and 2'-alkyl-, the 1- and 2-cycloalkyl-,

the 1- and 2'-aryl-, the 1'- and 2'-aralkyland the N-acylderivatives of all of the above named compounds.

The 21-dihydrogen phosphate esters are prepared by the reaction of the corresponding 2l-iodo compound with a mixture of silver phosphate and phosphoric acid. Both the monoand dialkali metal salts may be obtained by neutralization of the dihydrogen phosphate ester with an alkali methoxide. Treatment with additional amounts of alkali methoxide will convert an N-acyl-steroid (R =acyl) into the free amine (R =H) dialkali metal salt from which the dihydrogen phosphate can be obtained by contacting with an ion exchange resin.

CI-IzOP O HQX The A, B, C and pyrazole rings are not shown in the above equation, as the substituent groups on these rings do not affect the course of reaction and in general are unchanged during reaction. R has the meaning above defined and X is halogen.

The 21-fluoro-17u-hydroxy-20 oxo 4,6 pre-gnadieno- [3,2-c] pyrazoles are prepared from the corresponding 17cc,

21-dihydroxy-20-oxo-4,6-pregnadieno-[3,2c]pyrazole 21- mesylate by heating with an alkali fluoride in a solvent to form a mixture of a 17a,21-epoxy-cornpound and the corresponding 21-fiuoro compound. These compounds are separated by partition chromatography, or by chromatography on a weak adsorbent such as silica gel. There is thus obtained the 21-fluoro-derivatives of all of the compounds named in columns 2-4. The 2l-flu oro-derivatives are represented by structures A and B:

wherein R R R R and X have the significance above described. All of the 4,6-pregnadieno-[3,2-c]pyrazoles described in the foregoing structures form salts such as the hydrochloride, sulfate, chlorate, perchlorate, picrate, and trichloroacetate, on treatment with the corresponding acid. Formation of crystalline salts, especially the hydrochloride salts, provides a means of isolating the 4,6-pregnadieno-[3,2-c] pyrazoles.

A further embodiment of our invention comprises novel pharmaceutical compositions containing the novel 4,6- pregnadieno-[3,2-c]pyrazoles exemplified in the foregoing structures.

The following examples illustrate methods of carrying out the present invention but it is to be understood that these examples are given for purposes of illustration and not of limitation. Details of the above described reactions are to be found in the examples.

Example 1 To a suspension of 25.0 g. of 11 8,17a,21-trihydroxy- 4,6-pregnadiene-3,20-dione in 1.5 l. of alcohol free chloroform cooled to about 5 C. in an ice bath is added with constant stirring 750 ml. of cold, concentrated hydrochloric acid and then 750 ml. of formalin (low in methanol). The mixture is removed from the ice bath and stirred at room temperature for 7 hours. The layers are separated and the aqueous phase is back-extracted twice with chloroform. The combined organic layers are washed twice with a 5% solution of sodium bicarbonate, and twice with a saturated salt solution. The solution is dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue is triturated with methanol to afford a crystalline solid. This material contains no detectable amount of starting material by paperstrip chromatography but shows two U.V. absorbing spots near the solvent front (methanol-formamide 2:1 vs. benzene-n-hexane 1:1). A 2.425 g. aliquot is recrystallized three times from a mixture of benzene and n-hexane to give 17u,20,20,21-bis (methylenedioxy)-1 1,8-hydroxy-4,6- pregnadiene-3-one which is used in the subsequent step of the synthesis without further purification.

A solution of 400 mg. of 17a,20,20,21-bis(methylenedioxy)-11/3-hydroxy-4,6-pregnadiene-3-one in 4 ml. of pyridine is added to the complex formed by the addition of 400 mg. of chromium trioxide to 4 ml. of pyridine. The mixture is swirled until thoroughly mixed and then allowed to stand at room temperature overnight. The reaction mixture is poured into water, and the aqueous mixture is extracted with ether and then twice with ethyl acetate. The combined ether and ethyl acetate extracts are washed with dilute aqueous sulfuric acid at about 0 C., and then with water until neutral. The organic solvent layer is then dried, the solvents are evaporated therefrom in vacuo, and the residual crystalline material is purifled-by crystallization from a mixture of ethyl acetate and ether to give 17a,20,20,2l-bis(methylenedioxy)4,6-pregnadiene-3,11-dione.

The l7oz,20,20,2l bis(methylenedioxy) 4,6-pregnadiene-3,11-dione (1.350 g.) is dissolved in 23 ml. of dry, hot benzene and the resulting solution is cooled to room temperature and treated with 0.96 ml. of freshly distilled ethyl formate. The air in the system is replaced with nitrogen and 560 mg. of sodium hydride (as a 58% dispersion in mineral oil) is added. The system is again evacuated and filled with nitrogen, and the mixture is stirred magnetically at room temperature overnight. The mixture is poured into an excess of a saturated aqueous solution of sodium dihydrogen phosphate and the product is extracted four times with benzene. The organic extracts are washed three times with water and dried over sodium sulfate. Removal of the solvent gives the crude product which is dissolved in ether and purified as the sodium salt by extraction into a 10% solution of sodium carbonate. The aqueous alkaline extracts are again acidified with an excess of a saturated aqueous solution of sodium dihydrogen phosphate and extracted into ether and into chloroform. The combined organic extracts are dried over sodium sulfate and evaporated to dryness to give 17u,20,20,21 bis(methylenedioxy) 2-hydromethylene-4,6-pregnadiene-3,l l-dione.

The 17a,20,20,2 1 -bis (methylenedioxy) -2-hydroxymethylene-4,6-pregnadiene-3,1l-dione (850 mg.) is dissolved in 9.2 ml. of absolute ethanol and treated with a solution of 0.16 ml. of hydrazine hydrate dissolved in 0.16 ml. of absolute ethanol. The mixture is refluxed in a nitrogen atmosphere for about 45 minutes and then evaporated to dryness under reduced pressure. The residue is washed three times with cold water and the resulting amorphous solid is dried at 80 C. for 1 hour in high vacuum to give 17a,20,20,21 bis(methylenedioxy) 11 oxo-4,6-pregnadieno-[3,2-c]pyrazole.

To a solution of 100 mg. of 17a,20,20,21-bis(methylenedioxy)-11-oxo-4,6-pregnadieno-[3,2-c] pyrazole in 2 ml. of pyridine is added one milliequivalent of acetic anhydride. The mixture is allowed to stand overnight at room temperature. A mixture of ice and water is then added. After standing for about 30 minutes, the product is extracted with ethyl acetate. The ethyl acetate extract is washed successively with water, ice-cold 1 N sulfuric acid (until the pH of the aqueous layer is 1-3), saturated aqueous sodium bicarbonate (until the pH of the aqueous layer is 8), and water (until the aqueous layer is neutral). The ethyl acetate solution is dried with anhydrous sodium sulfate. The solvent is then distilled at about 40 C. in vacuo to afford the N-acetyl-l7a,20,20,21-bis(methylenedioxy)-1l-oxo-4,6-pregnadieno-[3,2-c]pyrazole which is isolated by the addition of water and filtration.

In accordance with the above procedure, but using an equivalent quantity of another acylating agent in place of acetic anhydride, there is obtained the corresponding N-acyl derivative.

The N acetyl 17u,20,20,21-bis(methylenedioxy)-1loxo-4,6-pregnadieno-[3,2-c]pyrazole (720 mg.) is heated in a steam bath with 24 ml. of a 60% aqueous solution of formic acid for about 30 minutes. The excess reagent is removed in vacuo using a water bath at about 50 C. as the source of heat. The residue is flushed four times with n-hexane and then dried at 60 C. in high vacuum to give an amorphous solid which is a mixture of N-acetyl- 170:,21 dihydroxy 11,20-dioxo-4,6-pregnadieno-[3,2-c] pyrazole and N-acetyl-2l-formyloxy-17a-hydroxy-11,20- dioxo-4,6-pregnadieno-[3,2-c]pyrazole, which compounds are separated by chromatography.

A 500 mg. aliquot of this crude product is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with water, filtered and dried to constant weight to give 17a,21-dihydroxy-11,20 tdioxo-4,6-pregn adieno- 3,2-c] pyrazole.

To a solution of 100 mg. of N-acetyl-17a,21-dihydroxy- '1l,20-dioxo-4,6-pregnadieno-[3,2-c1pyrazole in 2 ml. of pyridine is added one milliequivalent of acetic anhydride.

The mixture is allowed to stand overnight at room temperature. A mixture of ice and water is then added.

.After standing for about 30 minutes, the product is extracted with ethyl acetate. The ethyl acetate extract is washed successively with water, ice-cold 1 N sulfuric acid (until the pH of the aqueous layer is 1-3), saturated aqueous sodium bicarbonate (until the pH of the aqueous layer is 8), and water (until the aqueous layer is neutral). The ethyl acetate solution is dried with anhydrous sodium sulfate. The solvent is then distilled at about 40 C. in vacuo to afford the N-acetyl-17u,21-dihydroxy-11,20- dioxo-4,6-pregnadieno-[3,2-c]pyrazole 21-acetate which is isolated by the addition of water and filtration.

In accordance with the above procedure, but using an equivalent quantity of another acylating agent in place of 16 acetic anhydride, there is obtained the corresponding N- acetyl 17a,21 dihydroxy-11,20-dioxo-4,6-pregnadieno- [3,2-c]pyrazole 21-acylate.

In accordance with the above procedure, but starting with the 17a,21-dihydroxy-11,20-dioxo-4,6-pregnadieno- [3,2-c]pyrazole, and using two milliequivalents of another acylating agent there is obtained the corresponding N- acyl-Zl-acylate thereof.

A solution of 5.73 g. of N-acetyl-17a,21-dihydroxy- 11,20-dioxo-4,6-pregnadieno-[3,2-c]pyrazole 21-acetate in 60 ml. of (v./v.) acetic acid is refluxed for 1.5 hours. This solution is diluted with 400 ml. of ice-water and extracted with ethyl acetate. The ethyl acetate extracts are washed with water and with saturated sodium bicarbonate solution, dried, and evaporated to dryness in vacuo. Recrystallization of the resulting product affords the 170:,21 dihydroxy 11,20 dioxo-4,6-pregnadieno-[3,2-c] pyrazole 21-acetate.

To a solution of mg. of N-acetyl-17ot,2l-dihydroxy- 11,20-dioxo-4,6-pregnadieno-[3,2-c]pyrazole in 0.5 ml. of pyridine, cooled to 0 C. is added 0.015 ml. of methane sulfonyl chloride. The resulting mixture is allowed to stand at a temperature of approximately 0 C. for a period of approximately one hour. Water is then added to the reaction mixture and the precipitate which forms is recovered by filtration, washed with water, and dried to give N-acetyl-17a,2l-dihydroxy-l1,20-dioxo-4,6-preg nadieno-[3,2-c] pyrazole 2l-mesylate.

To a 180 mg. of N-acetyl-17a,2l-dihydroxy-l1,20-dioxo-4,6-pregnadieno-[3,2 c]pyrazole 21 mesylate dissolved in 10 ml. of acetone is added 300 mg. of sodium iodide. The resulting mixture is heated at reflux temperature for a period of approximately 1 hour, and the reaction solution is cooled to room temperature and diluted with water. The material which precipitates is recovered by filtration, washed with water, and dried to give N-acetyl-l7a-hydroxy-2l-iod-o-l1,20-dioxo-4,6- pregnadieno- 3 ,2-c] pyrazole.

The N acetyl 17oz hydroxy 21 iodo 11,20- dioxo-4,6-pregnadieno-[3,2-c]pyrazole is dissolved in a mixture of 5 ml. of water and 5 ml. of ethanol. To the resulting suspension is added 500 mg. of sodium bisulfite and the mixture is heated under reflux for a period of about 1 hour. The reaction solution is cooled, diluted with water, and the material which separates is recovered by filtration. The product is washed with water, dried and recrystallized from ethyl acetate to give N-acetyl-l7othydroxy 11,20 dioxo 4,6 pregnadieno [3,2-c] pyrazole.

A 500 mg. aliquot of the above compound is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.5 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with water, filtered and dried to constant weight to give 17u-hydroxy-11,20- dioxo-4,6-pregnadieno- 3 ,2-c] pyrazole.

To a solution of 62 mg. of N-acetyl-17ot,2l-dihydroxy- 11,20 dioxo 4,6 pregnadieno [3,2-c]pyrazole 21- mesylate in 1 ml. of freshly distilled anhydrous dimethyl formamide is added enough anhydrous potassium fluoride to assure a saturated solution. The mixture is heated at C. for 20 hours. Water is added to the cooled solution and the product is extracted into chloroform, dried over sodium sulfate and evaporated to dryness. The resulting product is a mixture of N-acetyl-17ot,21- epoxy 11,20 dioxo 4,6 pregnadieno [3,2-c]pyrazole and N acetyl 21 fluoro 17a hydroxy 11, 20-dioxo-4,6-pregnadieno-[3,2-c1pyrazole, which compounds are separated by partition chromatography, or by chromatography on silica gel.

A 500 mg. aliquot of the above compound is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.5 ml. of a 1.33 N solution of sodium methoxide in rhethanol at room temperature under nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with water, filtered and dried to constant weight to give 21-fluorol7ot-hydroxy-11,20-dioxo 4,6 pregnadieno [3,2 c] pyrazole.

In accordance with the above procedures, but starting with the 11 fl,17oc,21 trihyd-roxy 16a methyl 4,6-pregnadiene-3,20-dione or 1113,170:,2l-trihydroxy-lGfi-methyl- 4,6-pregnadiene-3,20-dione in place of the 1l,l3,l7a,2l-

trihydroxy-4,6-pregnadiene-3,ZO-dione, there are obtained as products the corresponding l7ot,21-dihydroxy-16amethyl 11,20 dioxo 4,6 pregnadieno [3,2-c1pyrazole or 17oc,21 dihydroxy 16B methyl 11,20- dioxo 4,6 pregnadieno [3,2-c1pyrazole, and the N- acyl-, the 2l-acylate, and the N-acyl-2l-acylate derivatives thereof; the 17m hydroxy 16a methyl 11, 20 dioxo 4,6 pregnadieno [3,2 c]pyrazo1e or 17ahydroxy 16B methyl 11,20 dioxo 4,6 pregnadieno [3,2-c]pyrazole and the N acyl derivatives thereof; and the Zl-fiuOIO-17u-hYClIOXY-160z-1'I16'thYl- 11,20 dioxo 4,6 pregnadieno [3,2-c]pyrazole or 21 fluoro 170a hydroxy 16B methyl 11,20 dioxo 4,6 pregnadieno [3,2-c1pyrazole and the N-acyl derivatives thereof.

In accordance with the above procedures, but starting with the 11,8,17a,21 trihydroxy 16 methylene 4,6- pregnadiene-3,20-dione in place of the 1lfl,17ot,21-trihydroxy-4,6-pregnadiene-3,20-dione, there are obtained as products the corresponding 17a,2l-dihydroxy-16-rnethylene 11,20 dioxo 4,6 pregnadieno [3,2-c1pyrazole and the N-acyl-, the 2l-acylate, and the N-acyl-Zlacylate derivatives thereof; the 17a-hydroxy-l6-methylene 11,20 dioxo 4,6 pregnadieno [3,2-c1pyrazole and the N-acyl derivatives thereof; and the 21- fiuoro 17oz hydroxy 16 methylene 11,20 dioxo- 4,6-pregnadieno-[3,2-c1pyrazole and the N-acyl derivatives thereof.

Example 2 To a suspension of 25.0 g. of 6-fiuoro-l1fl,17o-21-trihydroxy-4,6-pregnadiene-3,20-dione in 1.5 liters of alcohol-free chloroform cooled to about C. in an ice bath is added with constant stirring 750 ml. of cold, concentrated hydrochloric acid and then 750 ml. of formalin (low in methanol). The mixture is removed from the ice bath and stirred at room temperature for 7 hours. The layers are separated and the aqueous phase is backextracted twice with chloroform. The combined organic layers are washed twice with a 5% solution of sodium bicarbonate, and twice with a saturated salt solution. The solution is dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue is triturated with methanol to afford a crystalline solid. This material contains no detectable amount of starting material by paperstrip chromatography but show two U.V. absorbing spots near the solvent front (methanolf-ormamide 2:1 vs. benzene-n-hexane 1:1). A 2.425 g. aliquot is recrystallized three times from a mixture of benzene and n-hexane to give 6-fluoro-17a,20,20,21-bis (methylene dioxy) 11,8 hydroxy 4,6 pregnadiene- 3-one, which is used in the subsequent step of the synthesis without further purification.

The 17oc,20,20,21 bis(methylenedioxy) 6 fluoro- 1lB-hydroxy-4,6-pregnadiene-3-one (1.350 g.) is dissolved in 23 ml. of dry, hot benzene and the resulting solution is cooled to room temperature and treated with 0.96 ml. of freshly distilled ethyl formate. The air in the system is replaced with nitrogen and 560 mg. of sodium hydride (as a 58% dispersion in mineral oil) is added. The system is again evacuated and filled with nitrogen, and the mixture is stirred magnetically at room temperature overnight. The mixture is poured into an excess of a saturated aqueous solution of sodium dihydrogen phosphate and the product is extracted four times with benzene. The organic extracts are washed three times with water and dried over sodium sulfate. Removal of the solvent gives the crude product which is dissolved in ether and purified as the sodium salt by extraction int-o a 10% solution of sodium carbonate. The aqueous alkaline extracts are again acidified with an excess of a saturated aqueous solution of sodium dihydrogen phosphate and extracted into ether and into chloroform. The combined organic extracts are dried over sodium sulfate and evaporated to dryness to give 17a,20,20,21-bis (methylenedioxy) -6-fluoro 11 [i-hydroxy- 2-hydroxymethylene-4,6-pregnadiene-3-one.

The 17a,20,20,21 bis(methylenedioxy) 6 fluorollB hydroxy 2 hydroxyrnethylene 4,6 pregnadiene- 3-one (850 mg.) is dissolved in 9.2 ml. of absolute ethanol and treated with a solution of 0.16 ml. of hydrazine hydrate dissolved in 0.16 ml. of absolute ethanol. The mixture is refluxed in a nitrogen atmosphere for about 45 minutes and then evaporated to dryness under reduced pressure. The residue is washed three times with cold water and the resulting amorphous solid is dried at 80 C. for 1 hour in high vacuum to give 17a, 20,20,21-bis (methylenedioxy) 6 fiuoro 11B hydroxy- 4,6-pregnadieno-[3,2-c]pyrazole.

To a solution of 100 mg. of 17a,20,20,21-bis(methylenedioxy)-G-fluoro 115 hydroxy 4,6 pregnadieno- [3,2-c]pyrazole in 2 ml. of pyridine is added one milliequivalent of acetic anhydride. The mixture is allowed to stand overnight at room temperature. A mixture of ice and water is then added. After standing for about 30 minutes, the product is extracted with ethyl acetate. The ethyl acetate extract is washed successively with water, ice-eold l N sulfuric acid (until the pH of the aqueous layer is 1-3), saturated aqueous sodium bicarbonate (until the pH of the aqueous layer is 8), and water (until the aqueous layer is neutral). The ethyl acetate solution is dried with anhydrous sodium sulfate. The solvent is then distilled at about 40 C. in vacuo to afford the N- acetyl l7u,20,20,21 bis(methylenedioxy) 6 fluorollfi hydroxy 4,6 pregnadieno [3,2 c] pyrazole which is isolated by the addition of water and filtration.

In accordance with the above procedure, but using an equivalent quantity of another acylating agent in place of the acetic anhydride, there is obtained the corresponding N-acyl derivative.

The N acetyl 17a,20,20,21-bis(methylenedioxy)- 6 fluoro 11p hydroxy 4,6 pregnadieno [3,2 c] pyrazole (720 mg.) is heated in a steam bath with 24 ml. of a 60% aqueous solution of formic acid for about 30 minutes. The excess reagent is removed in vacuo using a water bath at about 50 C. as the source of heat. The residue is flushed four times with n-hexane and then dried at 60 C. in high vacuum to give a solid which is a mixture of N-acetyl-6-fiuoro-11;8,17a,2l-trihydroxy-20 oxo-4,6-pre-gnadieno-[3,2-c]pyrazole and N-acetyl-6- fluoro-Zl-formyloxy-l1/3,17u-dihydroxy 20 oxo 4,6- pregnadieno-[3,2-c]pyrazole, which compounds are separated by chromatography.

A 500 mg. aliquot of this crude product is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmos phere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with water, filtered and dried to constant weight to give 6-fluorol1B,17a,2l-trihydroxy 20 oxo 4,6 pregnadieno- [3.2-c]pyrazole.

To a solution of mg. of N-acetyl-6-fluoro-ll 8, 17a,21-trihydroxy-20-oxo 4,6 pregnadieno L [3,2-c] pyrazole in 2 ml. of pyridine is added one milliequivalent of acetic anhydride. The mixture is allowed to stand overnight at room temperature. A mixture of ice and water is then added. After standing for about 30 minutes, the product is extracted with ethyl acetate. The ethyl acetate extract is Washed successively with water, ice-cold 1 N sulfuric acid (until the pH of the aqueous layer is 1-3), saturated aqueous sodium bicarbonate (until the pH of the aqueous layer is 8), and water (until the aqueous layer is neutral). The ethyl acetate solution is dried with anhydrous sodium sulfate. The solvent is then distilled at about 40 C. in vacuo to afford the N-acetyl-6 fluoro ll}9,l7oc,21 trihydroxy 20- oxo-4,6-pregnadieno-[3,2-c]pyrazole 21-acetate which is isolated by addition of water and filtration.

In accordance with the above procedures, but using an equivalent quantity of another acylating agent in place of the acetic anhydride, there is obtained the corresponding N-acetyl 6 fluoro 11fl,17a,21 trihydroxy 20- oxo 4,6 pregnadieno [3,2-c]pyrazole 21 acylate.

In accordance with the above procedure, but starting with the 6 fluoro 1l 3,17a,21 trihydroxy 2O oxo- 4,6-pregnadieno-[3,2-c]pyrazole, and using two equivalents of another acylating agent there is obtained the corresponding N-acyl-21-acylate thereof.

A solution of 5.73 g. of N-acetyl-6-fluoro-11u,17a, 21-trihydroxy 20 oxo 4,6 pregnadieno [3,2-c] pyrazole 21-acetate in 60 ml. of 80% (v./v.) acetic acid is refluxed for 1.5 hours. This solution is diluted with 400 ml. of ice-water and extracted with ethyl acetate. The ethyl acetate extract is washed with water and with saturated sodium bicarbonate solution, dried, and evaporated to dryness in vacuo. Recrystallization of the resulting product affords the 6-fluoro-17a,2l-dihydroxy- 11,20-dioxo-4,6 pregnadieno [3,2-c1pyrazole 12 acetate.

To a solution of 85 mg. of N-acetyl-6-fluoro-11fi,17a,21- trihydroxy-20-oxo-4,6pregnadieno [3,2 c]pyrazole in 0.5 ml. of pyridine, cooled to C. is added 0.015 ml. of methane sulfonyl chloride. The resulting mixture is allowed to stand at a temperature of approximately 0 C. for a period of approximately 1 hour. Water is then added to the reaction mixture and the precipitate which forms is recovered by filtration, washed with water, and dried to give N-acetyl-6-fluoro-11B,17a,21-trihydroxy- 20-oxo 4,6 pregnadieno [3,2 c]pyrazole 21 mesylate.

To 180 mg. of N-acetyl-6-fluoro-11/8,17u,21-trihydroxy- 2O oxo 4,6 pregnadieno [3,2 cJpyrazole 21 mesylate dissolved in 10 ml. of acetone is added 300 mg. of sodium iodide. The resulting mixture is heated at reflux temperature for a period of approximately 1 hour, and the reaction solution is cooled to room temperature and diluted with water. The material which precipitates is recovered by filtration, washed with water, and dried to giveN acetyl 6 fluoro 113,170: dihydroxy 2liodo-20-oxo-4,6-pregnadieno-[3,2-c]pyrazole.

The N acetyl 6 fluoro 1lfl,17u dihydroxy 2liodo-20-oxo-4,6-pregnadieno-[3,2-c]pyrazole is dissolved in a mixture of 5 ml. of water and 5 ml. of ethanol. To the resulting suspension is added 500 mg. of sodium bisulfite and the mixture is heated under reflux for a period of about one hour. The reaction solution is cooled, diluted with water, and the material which separates is recovered by filtration. The product is washed with water, dried and recrystallized from ethyl acetate to give Naacetyl 6 fluoro ll[3,l7oc dihydroxy 20 oxo 4,6- pregnadieno-[3,2-c]pyrazole.

A 500 mg. aliquot of the above compound is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution'of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with water, filtered and dried to constant weight to give 6-fluoro-llfi, l7a-dihydroxy-20-oxo-4,6rpregnadieno-[3,2-c]pyrazole.

To a solution of 62 mg. of N-acety1-6-fiu'oro-11517a, 21 trihydroxy 20 oxo 4,6 pregnadieno [3,2-c] pyrazole 21-mesylate in 1 ml. of freshly distilled anhydrous dimethylformamide is added enough anhydrous potassium fluoride to assure a saturated solution. The mixture is heated at C. for 20 hours. Water is added to the cooled solution and the product is extracted into chloroform, dried over sodium sulfate and evaporated to dryness. The resulting product is a mixture of N-acetyl- 17a,21 epoxy 6 fluoro 11B hydroxy 2O oxo 4,6- pregnadieno-[3,2-cjpyrazdle and N-acetyl-6,21-difluoro- 1lfi,l7oc dihydroxy 20 oxo 4,6 pregnadieno [3,2-c] pyrazole Which compounds are separated by partition chromatography, or by chromatography on silica gel.

In accordance with the above procedures, but starting with the corresponding N-acyl derivatives, there are obtained as products the N-acyl-6-fluoro-11B,17o-dihydroxy- 20-oxo-4,6-pregnadieno-[3,2-c]pyrazole and the N-acyl-6, 21 difluoro 1113,1711 dihydroxy 2O oxo 4,6 pregnadieno-[3,2-c]pyrazole.

A 500 mg. aliquot of the above compound is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n} hexane. The residue is washed with water, filtered and dried to constant weight to give the 6,21-difluoro-1l/i,l7 x dihydroxy-20-oxo-4,6-pregnadieno-[3,2-c1pyrazole.

In accordance with the above procedures, but starting with the 1 1B,l7a,21-trihydroxy-6,l6a-dimethyl-4,6-pregnadiene-3,20-dione in place of the 6-fluoro-ll/3,l7a,21-trihydroxy-4,6-pregnadiene-3,20-dione there are obtained as products the corresponding l1/3,l7a,2l-trihydroxy-6,16adimethyl 20 oxo 4,6-pregnadieno-[3,2-c]pyrazole and the N-acyl-, the Zl-acylate, and the N-acyl-21-acylate derivatives thereof; the llfi,l7a-dihydroxy-l6rx-dimethyl- 20-oxo-4,6-pregnadieno[3,2-c]pyrazole and the N-acyl derivative thereof; and the 2l-fluoro-l1/3,17a-dihydroxy- 6,160: dimethyl 20 oxo 4,6 pregnadieno [3,2-c] pyrazole and the N-acyl derivative thereof.

Example 3 To a suspension of 25.0 g. of 11fi,17a,21-trihydroxy-6- methyl-4,6-pregnadiene-3,20-dione in 1.5 l. of alcoholfree chloroform cooled to about 5 C. in an ice bath is added with constant stirring 750 ml. of cold, concentrated hydrochloric acid and then 750 ml. of formalin (low in methanol). The mixture is removed from the ice bath and stirred at room temperature for 7 hours. The layers are separated and the aqueous phase is back-extracted twice with chloroform. The combined organic layers are washed twice with a 5% solution of sodium bicarbonate, and twice with a saturated salt solution. The solution is dried over magnesium sulfate and evaporated under reduced pressure. The residue is triturated with methanol to afford a crystalline solid. This material contains no detectable amount of starting material by paperstrip chromatography but shows two U.V. absorbing spots near the solvent front (methanol-formamide 2:1 vs. benzenen-hexane 1:1). A 2.425 g. aliquot is recrystallized three times from a mixture of benzene and n-hexane to give c,20,20,21 bis(methylenedioxy) 1113 hydroxy 6- methyl-4,6-pregnadiene-3-one which is used in the subsequent step of the synthesis without further purification.

A solution of 400 mg. of 17a,20,20,21-bis(methylenedioxy) 116 hydroxy 6 methyl 4,6 pregnadiene 3- one in 4 ml. ofv pyridine is added to the complex formed by the addition of 400 mg. of chromium trioxide to 4 ml. of pyridine. The mixture is swirled until thoroughly mixed and then allowed to stand at room temperature overnight. The reaction mixture is poured into water, and the aqueous mixture is extracted with ether and then twice with ethyl acetate. The combined ether and ethyl acetate extracts are washed with dilute aqueous sulfuric 21 'acid at about C., and then water until neutral. The organic solvent layer is then dried, the solvents are evaporated therefrom in vacuo, and the residual crystalline material is purified by crystallization from a mixture of ethyl acetate and ether to give 17ot,20,20,21-bis(methylenedioxy) -6-methyl-4,6-pregnadiene-3, l l-dione.

The 17a,20,20,21 bis(methylenedioxy)-6-methyl-4,6- pregnadiene-3,11-dione (1.350 g.) is dissolved in 23 ml. of dry, hot benzene and the resulting solution is cooled to room temperature and treated with 0.96 ml. of freshly distilled ethyl formate. The air in the system is replaced with nitrogen and 560mg. of sodium hydride (as a 58% dispersion in mineral oil) is added. The system is again evacuated and filled with nitrogen, and the mixture is stirred magnetically at room temperature overnight. The mixture is poured into an excess of a saturated aqueous solution of sodium dihydrogen phosphate and the product is extracted four times with benzene. The organic extracts are washed three times with water and dried over sodium sulfate. Removal of the solvent gives the crude product which is dissolved in ether and purified as the sodium salt by extraction into a solution of sodium carbonate. The aqueous alkaline extracts are again acidified with an excess of a saturated aqueous solution of sodium dihydrogen phosphate and extracted into ether and into chloroform. The combined organic extracts are dried over sodium sulfate and evaporated to dryness to give 17a,20,20,21-bis(methylenedioxy)-2-hydroxymethylene-6-methyl4,61pregnadiene-3 ,1 l-dione.

The 17cc,20,20,21-bis (methylenedioxy) -2-hyd roxymethylene-6-methyl-4,6-pregnadiene-3,1l-dione (850 mg.) is dissolved in 9.2 ml. of absolute ethanol and treated with a solution of 0.16 ml. of hydrazine hydrate dissolved in 0.16 ml. of absolute ethanol. The mixture is refluxed in a nitrogen atmosphere for about 45 minutes and then evaporated to dryness under reduced pressure. The residue is washed three times with cold water and the resulting amorphous solid is dried at 80 C. for 1 hour in high vacuum to give 17u,20,20,2l-bis(rnethylenedioxy)- G-methyl-1 1-oxo-4,6-pregnadieno-[3,2-c1pyrazole.

To a solution of 100 mg. of 17a,20,20,2l-bis(methylenedioxy -6-methyl-l 1-oxo-4,6-pregnadieno- 3,2-c] pyrazole in 2 ml. of pyridine is added one milliequivalent of acetic anhydride. The mixture is allowed to stand overnight at room temperature. A mixture of ice and water is then added. After standing for about 30 minutes, the product is extracted with ethyl acetate. The ethyl acetate extract is washed successively with water, ice-cold 1 N sulfuric acid (until the pH of the aqueous layer is 1-3), saturated aqueous sodium bicarbonate (until the pH of the aqueous layer is 8) and water (until the aqueous layer is neutral). The ethyl acetate solution is dried with anhydrous sodium sulfate. The solvent is then distilled at about 40 C., in vacuo to atford the N-acetyl-17a,20, 20,21-bis(methylenedioxy)-6-methyl-11-oxo-4,6apregnadieno-[3,2-c]pyrazole, which is isolated by the addition of water and filtration.

In accordance with the above procedure, but using an equivalent quantity of another acylating agent in place of the acetic anhydride, there is obtained the corresponding N-acyl derivative.

The N-acetyl 17a,20,20,21 bis(methylenedioxy) 6- methyl-1l-oxo-4,6-pregnadieno-[3,2-c]pyrazole (720 mg.)

is heated on a steam bath with 24 ml. of a 60% solution in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with water, filtered and dried to constant weight to give l7a,21-dihydroxy-6-methyl-11,20-dioxo 4,6 pregnadieno [3,2 c] pyrazole.

To a solution of mg. of N-acetyl-l7a,2l-dihydroxy- 6-methyl-l 1,20-dioxo-4,6-pregnadieno-[3,2-c] pyrazole in 2 ml. of pyridine is added one milliequivalent of acetic anhydride. The mixture is allowed to stand overnight at room temperature. A mixture of ice and water is then added. After standing for about 30 minutes, the product is extracted with ethyl acetate. The ethyl acetate extract is washed successively with water, ice-cold 1 N sulfuric acid (until the pH of the aqueous layer is 1-3), saturated aqueous sodium bicarbonate (until the pH of the aqueous layer is 8), and Water (until the aqueous layer is neutral). The ethyl acetate solution is dried with anhydrous sodium sulfate. The solvent is then distilled at about 40 C. in vacuo to afford the N-acetyl-17a,2l-dihydroxy-6-methyl- 11,20 dioxo-4,6-pregnadieno-[3,2-c]pyrazole 21-acetate which is isolated by addition of water and filtration.

In accordance with the above procedure, but using an equivalent quantity of another acylating agent in place of'acetic anhydride, there is obtained the corresponding N-acetyl 1711,21 dihydroxy 6-methyl-1'1,20-dioxo-4,6- pregnadieno- [3 ,2-c] pyrazole 2 l-acylate.

In accordance with the above procedures, but starting with the 17a,21 dihydroxy 6 methyl-11,20-dioxo-4,6- pregnadieno-[3,2c]pyrazole, and using two milliequivalents of another acylating agent, there is obtained the corresponding N-acyl- 17a,2 1-dihydroxy-6-methyl-1 1,20- dioxo-4,6-pregnadieno-[3,2-c]pyrazole 21-acylate.

A solution of 5.73 g. of the N-a'cetyl-Nail-dihydroxy- 6-methyl-11,20-dioxo-4,6-pregnadieno-[3,2-c]pyrazole 21- acetate in 60 ml. of 80% (v./v.) acetic acid is refluxed for 1.5 hours. This solution is diluted with 400 ml. of ice-water and extracted with ethyl acetate. The ethyl acetate extract is washed with Water and with saturated sodium bicarbonate solution, dried, and evaporated to dryness in vacuo. Recrystallization of the resulting pro-duct affords the :,21-dihydroxy-6-methyl-11,20- dioxo-4,6-pregnadieno-[3,2-c] pyrazole 21-acetate.

To a solution of 85 mg. of N-acetyl-lMil-dihydroxy- 6-methyl-1 1,20-dioxo-4,6-pregnadieno- [3 ,2-c] pyr-ozole in 0.5 ml. of pyridine, cooled to 0 C., is added 0.015 ml. of methane sulfonyl chloride. The resulting mixture is allowed to stand at a temperature of approximately 0 C. for a period of approximately one hour. Water is then added to the reaction mixture and the precipitate which forms is recovered by filtration, washed with water, and dried to give N-acetyl-175,2l-dihydroxy-G-methyl- 11,20-diox0-4,6-pregnadieno-[3,2-c1pyrazole 21-mesylate.

To mg. of N-acetyl-17a,21-dihydroxy-6-methyll 1,20-dioxo-4,6-pregnadieno-[3,2-c1pyrazole 21-mesylate dissolved in 10 ml. of acetone is added 300 mg. of sodium iodide. The resulting mixture is heated at reflux temperature for a period of approximately one hour, and the reaction solution is cooled to room temperature and diluted with water. The material which precipitates is recovered by filtration, washed with water, and dried to give N-acetyl-l7a-hydroxy-21-iodo-6-methyl-11,20-dioxo- 4,6-pregnadieno-[3,2-c1pyrazole.

The N acetyl 17a-hyroxy-2l-iodo-6-methyl-11,20-dioxo-4,6-pregnadieno-[3,2-c1pyrazole is dissolved in a mixture of 5 ml. of water and 5 ml. of ethanol. To the resulting suspension is added 500 mg. of sodium bisulfite, and the mixture is heated under reflux for a period of about 1 hour. The reaction solution is cooled, diluted with Water, and the material which separates is recovered by filtration. The product is washed with water, dried and recrystallized from ethyl acetate to give N acetyl 17a hydroxy 6 methyl 11,20 dioxo 4, 6 pregnadieno [3,2 c]pyrazole.

A 500 mg. aliquot of the above compound is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with water, filtered and dried to constant weight to give 17ahydroxy 6 methyl 11,20 dioxo 4,6 pregnadieno- [3,2 c] pyrazole.

To a solution of 62 mg. of N-acetyl-17a,2l-dihydroxy- 6 methyl 11,20 dioxo 4,6 pregnadieno [3,2 c] pyrazole 21-mesylate in 1 ml. of freshly distilled anhydrous dimethylformamide is added enough anhydrous potassium fluoride to assure a saturated solution. The mixture is heated at 110 C. for 20 hours. Water is added to the cooled solution and the product is extracted into chloroform, dried over sodium sulfate and evaporated to dryness. The resulting product is a mixture of N-acetyl-17u,21-epoxy-6-methyl-11,20-dioxo-4,6-pregnadieno-[3,2-c]pyrazole and N-acetyl-21-fluoro-17a-hydroxy 6 methyl 11,20 dioxo 4,6 pregnadieno [3, 2 c]pyrazole, which compounds are separated by partition chromatography, or by chromatography on silica gel.

In accordance with the above procedures, but starting with the 9a-fluoro-11B,17u,21-trihydroxy-4,6-pregnadiene-3,20-dione in place of the 11B,17a,21-trihydroxy- 4,6-pregnadiene-3,20-dione there are obtained as products the corresponding 9a-fluoro-17a,2l-dihydroxy-l1, 20-dioxo-4,6-pregnadieno-[3,2-c]pyrazole and the N- acyl-, the 21-acylate, and the N-acyl-21-acylate derivatives thereof in which the two acyl groups may be the same or different; the 9ot-fluoro-17a-hydroxy-l1,20- dioxo-4,6-pregnadieno-[3,2-c]pyrazole and the N-acyl derivatives thereof; and the 90:, 21-difluoro-17u-hydroxy- 11,20-dioxo-4,6-pregnadieno-[3,2-c]pyrazole and the N- acyl derivatives thereof.

In accordance with the above procedures, but starting with the 9a-fluoro-6-methyl-1l5,17a,21-trihydroxy-4,6- pregnadiene-3,20-dione in place of the 11B,17oc, 21-trihydroxy-6-methyl-4,6-pregnadiene-3,20-dione, there are obtained as products the corresponding 9OL-fiuOI'O-17vt, 21-dihydroxy- 6-methyl-11,20-dioxo-4,6-pregnadieno-[3,2- c]py-razole and the N-acyl-, the 21-acylate, and the N- acyl-2l-acylate derivatives thereof in which the two acyl groups may be the same or different; the 9a-fluoro-17ahydroxy-6-methyl-11,20-dioxo-4,6 pregnadieno [3,2 c] pyrazole and the N-acyl derivatives thereof; and the 9u,21 difluoro 17a hydroxy 6 methyl 11,20 dioxo- 4,6-pregnadieno-[3,2-c]pyrazole and the N-acyl derivatives thereof.

2 Example 4 To a suspension of 25.0 g. of 11 8,17a,21-trihydroxyt16a-methyl-4,6-pregnadiene-3,20-dione in 1.5 liters of alcohol-free chloroform cooled to about C. in an ice bath is added with constant stirring 750 ml. of cold, concentrated hydrochloric acid and then 750 ml. of formalin (low in methanol). The mixture is removed from the ice bath and stirred at room temperature for 7 hours. The layers are separated and the aqueous phase is back-extracted twice with chloroform. The combined organic layers are washed twice with a 5% solution of sodium bicarbonate, and twice with a saturated salt solution. The solution is dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue is triturated with methanol to afford a crystalline solid. This material contains no detectable amount of starting material by paperstrip chromatography. A 2.425 g. aliquot is recrystallized three times from a mixture of benzene and n-hexane to give 17a,20,20,21-bis (methylenedioxy) 11B hydroxy 16oz methyl 4,6-

24 pregnadiene-3-one which is used in the subsequent step of the synthesis without further purification.

The 17oc,20,20,21 bis(methylenedioxy)-llfi-hydroxy- 16u-methyl-4,6-pregnadiene-3-one (1.350 g.) is dissolved in 25 ml. of dry, hot benzene and the resulting solution is cooled to room temperature and treated with 0.96 ml. of freshly distilled ethyl formate. The air in the system is replaced with nitrogen and 560 mg. of sodium hydride (as a 58% dispersion in mineral oil) is added. The system is again evacuated and filled with nitrogen, and the mixture is stirred magnetically at room temperature overnight. The mixture is poured into an excess of a saturated aqueous solution of sodium dihydrogen phosphate and the product is extracted four times with benzene. The organic extracts are washed three times with water and dried over sodium sulfate. Removal of the solvent gives the crude product which is dissolved in ether and purified as the sodium salt by extraction into a 10% solution of sodium carbonate. The aqueous alkaline extracts are again acidified with an excess of a saturated aqueous solution of sodium dihydrogen phosphate and extracted into ether and into chloroform. The combined organic extracts are dried over sodium sulfate and evaporated to dryness to give 17a,20,20,21-bis (methylenedioxy) 115 iydroxy 2 hydroxymethylene- 16a-methyl-4,6-pregnadiene-3-one.

The 17a,20,20,21-bis(methylenedioxy)-11B-hydroxy-2- hydroxymethylene-l6u-methyl-4,6-pregnadiene-3-one (850 mg.) is dissolved in 9.2 ml. of absolute ethanol and treated with a solution of 0.16 ml. of hydrazine hydrate dissolved in 0.16 ml. of absolute ethanol. The mixture is refluxed in a nitrogen atmosphere for about 45 minutes and then evaporated to dryness under reduced pressure. The residue is washed three times with cold water and the resulting amorphous solid is dried at C. for 1 hour in high vacuum to give 17a,20,20,21-bis(methylenedioxy)- 1Iii-hydroxy-16a-methyl-4,6-pregn-adieno-[3,2-c]pyrazole.

To a solution of mg. of 17a,20,20,21-bis(methylenedioxy)-11fi-hydroxy 16cc methyl 4,6 pregnadieno- [3,2 c]pyrazole in 2 ml. of pyridine is added 0.5 ml. of acetic anhydride. The mixture is allowed to stand overnight at room temperature. A mixture of ice and water is then added. After standing for about 30 minutes, the product is extracted with ethyl acetate. The ethyl acetate extract is washed successively with water, ice-cold 1 N sulfuric acid (until the pH of the aqueous layer is 1-3), saturated aqueous sodium bicarbonate (until the pH of the aqueous layer is 8), and water (until the aqueous layer is neutral). The ethyl acetate solution is dried with anhydrous sodium sulfate. The solvent is then distilled at about 40 C. in vacuo to afford the N-acetyl 17a,20,20,21- bis (methylenedioxy) 11 B hydroxy 16oz methyl 4,6- pregnadieno-[3,2-c]pyrazole which is isolated by the addition of water and filtration.

In accordance with the above procedure, but using an equivalent quantity of another acylating agent in place of acetic anhydride there is obtained the corresponding N-acyl-steroid.

The N-acetyl 17a,20,20,2l-bis(methylenedioxy)-l1,8- hydroxy-16u-methyl 4,6 pregnadieno [3,2-c1pyrazole (720 mg.) is heated in a steam bath with 24 ml. of a 60% aqueous solution of formic acid for about 30 minutes. The excess reagent is removed in vacuo using a water bath at about 50 C. as the source of heat. The residue is flushed four times with n-hexane and then dried at 60 C. in high vacuum to give an amorphous solid which is a mixture of N-acetyl-I1,8,17u,21-trihydroxy-16amethyl-20-oxo-4,6-pregnadieno-[3,2-c]pyrazole and N- acetyl-2l-formyloxy-11,8,17a-dihydroxy 16oz methyl-20- oxo-4,6-pregnadieno [3,2-c]pyrazole which compounds are separated by chromatography.

A 500 mg. aliquot of this crude product is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmos- 25 phere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with water, filtered and dried to constant weight to give 11,8,17a-21- trihydroxy-16u-methyl-20-oxo 4,6 pregnadieno-[3,2-c] pyrazole.

To a solution of 100 mg. of N-acetyl-llfl,l7a,2l-trihydroxy-la-methyl-20 oxo 4,6 pregnadieno-[3,2-c1pyrazole in 2 ml. of pyridine is added one milliequivalent of acetic anhydride. The mixture is allowed to stand overnight at room temperature. A mixture of ice and water is then added. After standing for about 30 minutes, the product is extracted with ethylacetate. The ethyl acetate extract is washed successively with water, ice-cold 1 N sulfuric acid (until the pH of the aqueous layer is 13), saturated aqueous sodium bicarbonate (until the pH of the aqueous layer is 8), and water (until the aqueous layer is neutral). The ethyl acetate solution is dried with anhydrous sodium sulfate. The solvent is then distilled at about 40 C. in vacuo. The N-acetyl-l1B,l7er,21-trihydroxy 16a-methyl-20-oxo-4,6-pregnadieno- 3,2-c1pyrazole 21-acetate is then isolated by addition of water and filtration.

In accordance with the above procedures, but using an equivalent quantity of another acylating agent in place of acetic anhydride, there is obtained the corresponding N-acetyl-l1,8,17a,21-trihydroxy 16a methyl-20-oxo-4,6- pregnadieno-[3,2-c1pyrazole 21-acylate.

In accordance with the above procedure, but starting with the 11,8,17ot,21 trihydroxy-16a-methyl-20-oxo-4,6- pregnadieno-[3,2-c]pyrazole and using two milliequivalents of another acylating agent there is obtained the corresponding N-acyl-l 1/3, 1711,21-trihydroxy-16a-methyl-20- oxo-4,6-pregnadieno-[3,2-clpyrazole ZLacylate.

A solution of 5.73 g. of N-acetyl-11p,17a,21-trihydroxy- 16zx-methyl-20-oxo-4,6-pregnadieno [3,2-c]pyrazole 21- acetate in 60 ml. of 80% (v./v.) acetic acid is refluxed for 1.5 hours. This solution is diluted with 400 ml. of icewater and extracted with ethyl acetate. The ethyl acetate extractis washed with water and with saturated sodium bicarbonate solution dried, and evaporated to dryness in vacuo. Recrystallization of the resulting product affords 115,17a-21 trihydroxy 1604 methyl-20-oxo-4,6 pregnadieno-[3,2-c]pyrazole ZI-acetate.

To a solution of 85 mg. of N-acetyl-l1,8,17u,21-trihydroxy-16a-rnethyl-20-oxo 4,6 pregnadieno-[3,2-c]pyrazole in 0.5 ml. of pyridine, cooled to C., is added 0.015 ml. of methane sulfonyl chloride. The resulting mixture is allowed to stand at a temperature of approximately 0 'C. for a period of approximately one hour. Water is then added to the reaction mixture and the precipitate which forms is recovered by filtration, washed with water, and dried to give N-acetyl-l15,17a,2l-trihydroxy 16a methyl-20-oxo-4,6-pregnadieno-[3,2-c]pyrazole 21-mesylate.

To 180 mg. of N-acetyl-l1fl,17a,21-trihydroxy-16amethyl-20-oxo-4,6-pregnadieno- [3 ,2-c] pyrazole 2 l-mesylate dissolved in 10 ml. of acetone is added 300 mg. of sodium iodide. The resulting mixture is heated at reflux temperature for a period of approximately 1 hour, and the reaction solution is cooled to room temperature and diluted with water. The material which precipitates is recovered by filtration, washed with water, and dried to give N-acetyl-11B,17x dihydroxy 21 iodo 16oz methyl-20- oxo-4,6-pregnadieno-[3,2-c]pyrazole.

The N acetyl-l1B,17a-dihydroxy-21-iodo-16ot-methyl- 20-oxo-4,6-pregnadieno-[3,2-c]pyrazole is dissolved in a mixture of ml. of water and 5 ml. of ethanol. To the resulting suspension is added 500 mg. of sodium bisulfite, and the mixture is heated under reflux for a period of about 1 hour. The reaction solution is cooled, diluted with water, and the material which separates is recovered by filtration. The product is Washed with water, dried and recrystallized from ethyl acetate to give N-acetyl-l 1B,

ate and again with water.

17a dihydroxy 16cc methyl 20-oxo-4,6-pregnadieno- [3,2-c1pyrazole.

To a solution of 62 mg. of N-acetyl-l1fi,17a,21-trihydroxy 20-oxo-4,6-pregnadieno-[3,2-c1pyrazole 21-mesyl ate in 1 ml. of freshly distilled anhydrous dimethylformamide is added enough anhydrous potassium fluoride to assure a saturated solution. The mixture is heated at 110 C. for 20 hours. Water is added to the cooled solution and the product is extracted into chloroform, dried over sodium sulfate and evaporated to dryness. The resulting product is a mixture of N-acetyl-17u,21-epoxy- 11B hydroxy-16a-methyl-20-oxo-4,6-pregnadieno-[3,2-c] pyrazole and N-acetyl-Zl-fluoro-l1B,17a-dihydroxy-16umethyl 20-oxo-4,6-pregnadieno-[3,2-c1pyrazole, which compounds are separated by partition chromatography or by chromatography on silica gel.

A 500 mg. aliquot of the N-acetyl-21-fiuoro-1113,170:- dihydroxy 16a methyl-20-oxo-4,6-pregnadieno-[3,2-c] pyrazole is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with water, filtered and dried to constant weight to give the 21 fluoro 11,8,170: dihydroxy-l6tx-methyl-20-0xo- 4,6-pregnadieno- [3 ,2-c] pyrazole.

In accordance with the above procedures, but starting with the 11 ,8,17:1,21-trihydroxy-6-methyl-4,6 pregnadiene 3,20-dione in place of the 11B,17a,21-trihydroxy-16amethyl-4,6-pregnadiene-3,ZO-dione, there are obtained as products the corresponding 11fi,17a,21-trihydroxy-6- methyl-20-oxo-4,6-pregnadieno-[3,2-c]pyraz0le and the N-acyl-, the 21-acylate, and the N-acyl-Zl-acylate derivatives thereof in which the two acyl groups may be the same or different; the 11/5, 17a-dil1ydroxy-6-methyl-20-oxo- 4,6-pregnadieno-[3,2-c]pyrazole and the N-acyl derivatives thereof; and the 21-fluoro-11fi,17u-dihydroxy-6- methyl-20-oxo-4,6-pregnadieno-[3,2-c1pyrazole and the N-acyl derivatives thereof.

Example 5 To a suspension of 10 g. of c,l1[3-dlChlO1O-l7u,2ldihydroxy-4,6-pregnadiene-3,ZO-dione in 475 ml. of alcohol-free chloroform and 300 ml. of methylene chloride, cooled to about 5 C. in an ice bath, is added with constant stirring 189 ml. of cold, concentrated hydrochloric acid and then 189 ml. of formalin (low in methanol). The mixture is removed from the ice bath and stirred at room temperature for 2 hours. The layers are separated and the aqueous phase is back-extracted twice with chloroform. The combined organic layers are Washed with water, then with a 5% solution of sodium bicarbon- The solution is dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue is flushed three times with methanol. Hot methanol is then added and the product is filtered and then crystallized from a mixture of methylene chloride and n-hexane to give17a,20,20,2l-bis(methylenedioxy)-9a,11(3-dichlor0-4,6-pregnadiene-3-one.

The 17a,20,20,21-bis(methylenedioxy)-9m,11fl-dichloro- 4,6-pregnadiene-3-one (500 mg.) is suspended in 8.5 cc. of dry benzene and treated with 0.15 ml. of freshly dis tilled ethyl formate. The air in the system is replaced with nitrogen and 225 mg. of sodium hydride (as a 58% dispersion in mineral oil is added). The system is again evacuated and filled with nitrogen. The mixture is stirred under nitrogen for /2 hour after which time 0.2 ml. of ethyl formate is added and the mixture is stirred magnetically at room temperature overnight. The mixture is poured into an excess of a saturated aqueous solution of sodium dihydrogen phosphate and the product is extracted four times with benzene. The organic extracts are washed three times with Water and dried over sodium sulfate. Removal of the solvent gives the crude product which is dissolved in ether and purified as a sodium salt by extraction into a 10% solution of sodium carbonate. The aqueous alkaline extracts are again acidified with an excess of a saturated aqueous solution of sodium dihydrogen phosphate and extracted into ether. The combined organic extracts are dried over sodium sulfate and evaporated to dryness to give 17a,20,20,21-bis(methylenedioxy) 911,11fl-dichloro-2-hydroxymethylene-4,6-pregnadicne-3-one.

The 17a,20,20,21-bis(methylenedioxy)-9 x,1IB-dichloro- 2-hydroxymethylene-4,6-pregnadiene-3-one (65 mg.) is dissolved in 0.7 ml. of absolute ethanol and treated with a solution of 0.12 ml. of hydrazine hydrate dissolved in 0.12 ml. of absolute ethanol. The mixture is refluxed in a nitrogen atmosphere for about 45 minutes and then evaporated to dryness under reduced pressure. The residue is dissolved in chloroform and petroleum ether is added to give a solid which is 17a,20,20,21-biS(methylenedioxy) 90:,116 dichloro 4,6 pregnadieno-[3,2-c] pyrazole.

To a solution of 100 mg. of l7a,20,20,2l-bis(methylenedioxy) 9u,lla dichloro 4,6 pregnadieno-[3,2-c] pyrazole in 2 ml. of pyridine is added one milliequivalent of propionic anhydride. The mixture is allowed to stand overnight at room temperature. A mixture of ice and water is then added. After standing for about 30 minutes, the product is extracted with ethyl acetate. The ethyl acetate extract is washed successively with water, ice-cold l N sulfuric acid (until the pH of the aqueous layer is 1-3), saturated aqueous sodium bicarbonate (until the pH of the aqueous layer is 8), and water (until the aqueous layer is neutral). The ethyl acetate solution is dried with anhydrous sodium sulfate. The solvent is then distilled at about 40 C. in vacuo to afford the N-propionyl- 17a,20,20,21 bis(methylenedioxy) 9a,llB-dichloro-4,6- pregnadieno-[3,2-c]pyrazole which is isolated by the addition of water and filtration.

In accordance with the above procedures, but using an equivalent quantity of another acylating agent in place of propionic anhydride, there is obtained the corresponding N-acyl-derivative.

The N-propionyl-17oc,20,20,2l-bis(methylenedioxy)-9a, 11fi-dichloro-4,6-pregnadieno-[3,2-c]pyrazole (25 mg.) is heated on a steam bath with cc. of a 60% aqueous solution of formic acid for about 30 minutes. The excess reagent is removed under reduced pressure using a water bath at about 50 C. as the source of heat. The residue is flushed with n-hexane. The residue is then dissolved in acetone and precipitated with n-hexane to give an amorphous solid which is a mixture of N-propionyl-9a, 11 ,8-dichlor0-17a,2l-dihydroxy-20-oxo 4,6 pregnadieno- [3,2-c]-pyrazole and N-propionyl 9u,11B dichloro-21- formyl-oxy-17a-'hydroxy-20-oxo-4,6 pregnadieno-[3,2-c] pyrazole, which compounds are separated by chromatography.

A 500 mg. aliquot of this crude product is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alk-oxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with nhexane. The residue is washed with water, filtered and dried to constant weight to give 9a,llB-dichloro-l7a,21- dihydroxy-20-oxo-4,6-pregnadieno-[3,2-c]pyrazole.

To a solution of 100 mg. of N-propionyl-9a,11/3-dichloro-17a,21-dihydroxy-20-oxo 4,6 pregnadieno-[3,2- c]-pyr|azo1e in 2 ml. of pyridine is added 0.5 ml. of acetic anhydride. The mixture is allowed to stand overnight at room temperature. A mixture of ice and water is then added. After standing for about 30 minutes, the product is extracted with ethyl acetate. The ethyl acetate extract is washed successively with water, ice-cold 1 N sulfuric acid (until the pH of the aqueous layer is 1-3), saturated aqueous sodium bicarbonate (until the pH of the aqueous layer is 8), and water (until the aqueous layer is neutral).

The ethyl acetate solution is dried with anhydrous sodium sulfate. The solvent is then distilled at about 40 C., in vacuo. The product is then crystallized from a solvent; alternately, the product may be chromatographed on alumina to give the N-propionyl-9a,llfi-dichloro-17a,21- dihydroxy-20-oxo-4,6 pregnadieno-[3,2-c1pyrazole 21-acetate, which is isolated by crystallization of the appropriate eluate.

In accordance with the above procedure, but using an equivalent quantity of any other acylating agent in place of the acetic. anhydride, there is obtained the corresponding N-propionyl-9u,lIii-dichloro 1711,21 dihydroxy-20- oxo-4,6-pregnadieno- [3 ,2-c] pyrazole 21-aeylate.

In accordance with the above procedures, but starting with the 9a,1lfl-dichloro-l7 x,2l-dihydroxy 20 oxo-4,6- pregnadieno-[3,2-c]pyrazole and using two equivalents of another acylating agent there is obtained the correspondin g N-acyl-Zl-acyl-ate thereof.

A solution of 5.73 g. of N-propionyl-9a,lIB-dicholro- 17a,21 dihydroxy-20-oxo 4,6 pregnadieno[3,2-c]pyrazole 21-acetate in 60 ml. of (v./v.) acetic acid is refluxed for 1.5 hours. This solution is diluted with 400 ml. of ice-water and extracted with ethyl acetate. The ethyl acetate extract is washed with water and with saturated sodium bicarbonate solution, dried, and evaporated to dryness in vacuo. Recrystallization of the resulting product affords 904,1lfi-diChlOI'O-1701,21-ClihYdrOXY-ZO-OXO- 4,6-pregnadieno-[3,2-c1pyrazole 2l-acetate.

To a solution of mg. of N-propionyl-9a,11,B-dichloro-l7a,21-dihyd-roxy-20-oxo-4,6 pregnadieno-[3,2-c] pyrazole in 0.5 ml. of pyridine, cooled to 0 C., is added 0.015 ml. of methane sulfonyl chloride. The resuiting mixture is allowed to stand at a temperature of approximately 0 C. fora period of approximately 1 hour. Water is then added to the reaction mixture and the precipitate which forms is recovered by filtration, washed with water, and dried to give N-propionyl-9a,11fl-dichloro-17ot,21-dihydroxy 20 oxo 4,6-pregnadieno-[3,2 clpyrazole 21- mesylate.

To 180 mg. of N-propionyl-9a,11B-dichloro-17a,21-dihydroxy-20-oxo-4,G-pregnadieno-[3,2-c1pyrazole 21-mesylate dissolved in 10 ml. of acetone is added 300 mg. of sodium iodide. The resulting mixture is heated at reflux temperature for a period of approximately 1 hour, and the reaction solution is cooled to room temperature and diluted with water. The material which precipitates is recovered by filtration, washed with water, and dried to give N-propionyl-9a,11fl-dichloro-17a hydroxy-2l-iodo- 20-oxo-4,6-pregnadieno-[3,2 c]pynazole.

A 500 mg. aliquot of the above product is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with water, filtered and dried to constant weight to give N-propionyl-9a,11fl-dichloro-17a-hydroxy-21-iodo-20-oxo-4,6-pregnadieno-[3,2- c-]pyrazole.

The N-propionyl-9 a,11,B-dichloro-17u-hydroxy-21-iodo- 20-oxo-4,6-pr-egnadieno-[3,2-c]pyrazole is dissolved in a mixture of 5 ml. of water and 5 -ml. of ethanol. To the resulting suspension is added 500 mg. of sodium bisulfite, and the mixture is heated under reflux for a period of about 1 hour. The reaction solution is cooled, diluted with water, and the material which separates is recovered by filtration. The product is washed with water, dried and recrystallized from ethyl acetate to give N-propionyl- :,11fl-dich loro-17a-hydroxy-20 oxo 4,6 pregn-adieno- [3,2-c1pyrazole.

To a solution of 62 mg. of N-propionyl-9a,11fl-dichloro-17a,2l-dihydroxy-20-oxo-4,6 pregnadieno-[3,2-c] pyrazole 21-mesylate in 1 ml. of freshly distilled anhydrous dimethylformamide is added enough anhydrous mixture is heated at 110 C. for 20 hours.

potassium fluoride to assure a saturated solution. The Water is then added to the cooled solution and the product is extracted into chloroform, dried over sodium sulfate and evaporated to dryness. The resulting product is a mixture of N- propiony-l-9u,1lfi-dichlo-ro-l7ot,2l-epoxy-20 oxo-4,6-pregnadieno- 3 ,2-c]pyrazole and N-propionyl-9u,l lfl-dichloro- 21-fluoro-17a-hydroxy-20-oxo 4,6 pregnadieno-[3,2-c] pyrazole, which compounds are separated by partition chromatography or by chromatography on silica gel.

A 500 mg. aliquot of the crude product is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with water, filtered and dried to constant weight to give N-propionyl- 90,1 l B-dichloro-2 l-fluoro-17e-hydroxy-20-oxo-4,6 pregnadieno-[3,2-c]pyrazole.

In accordance with the above procedures, but starting with the 9a-bromo-1 1B-chloro-17or,21-dihydroxy-4,6-pregnadiene-3,20-dione in place of the 9a,11fi-dichloro-17a- 21-dihydroxy-4,6-pregnadiene-3,20-dione there are tained as products the corresponding 9a-bromo-l1fichloro-l7a,2l-dihydroxy-ZO-oxo 4,6pregnadieno-[3,2-c] pyrazole and the N-acyl-, the 21-acylate, and the N-acyl- 21-acylate derivatives thereof in which the two acyl groups may be the same or different; the 9a-bromo-11fi-chloro- 17a-hydroxy-20-oxo-4,6-pregnadieno-[3,2'c] p'yrazole and the N-acyl derivative thereof; and the 9a-bromo-11fl-chloro-2l-fluoro-17a-hydroxy-20-oxo-4,6 pre-gnadieno [3,2- c]pyrazole and the N-acyl derivatives thereof.

The 9a,1 1,8-dichloro-1711,21-dihydroxy-4,6-pregnadiene- 3,20-dione and the 9owbromo-l1,8-chloro-17a,2l-dihydroxy-4,6-pregnadiene-3,20-dione compounds, as well as the substituted derivatives thereof in columns 2-4, used as starting materials can be obtained in the following manner, starting from the corresponding 17a,21-dihydroxy-4- pregnene-3,20-dione.

A solution of 400 mg. of 17a,21-dihydroxy-4-pregnene- 3,20-dione in 2.0 ml. dimethyl formarnide, 0.8 ml. of pyridine and 0.4 ml. of methanesulfonyl chloride is allowed to stand at 75 C. for one hour. The mixture is cooled and water is added. The precipitate formed is filtered, washed with water, dried in air and purified by chromatography on alumina and elution with benzene. Crystallization gives 17a,21-dihydroxy-4,9( 1 1)-pregnadicue-3,20-dione.

To a solution of 100 mg. of 17u,21-dihydroxy-4,9(11)- pr egnadiene-3,20dione in 2 ml. of pyridine is added one milliequi-valent of acetic anhydride. The mixture is allowed to stand overnight at room temperature. A mixture of ice and water is then added. After standing for about 30 minutes, the product is extracted with ethyl acetate. The ethyl acetate extract is washed successively with water, ice-cold 1 N sulfuric acid (until the pH of the aqueous layer is 1-3), saturated aqueous sodium bicarbonate (until the pH of the aqueous layer is 8), and water (until the aqueous layer is neutral). The ethyl acetate solution is dried with anhydrous sodium sulfate. The solvent is then distilled at about 40 C. in vacuo to afford the 17a,21-dihydroxy-4,9(11)-pregnadiene-3,20- dione 2l-acetate which is isolated by the addition of water and filtration.

Toa stirred, cooled (0.5 C.) solution of 17a,21-dihydroxy-4,=9(11)-pregnadiene-3,20-dione-2l-acetate (1.0 g.) and lithium chloride (4.0 g.) in glacial acetic acid (40 ml.) is added N-chlorosuccinimide (383 mg, 1.1 equivalent) followed immediately by an anhydrous solution of hydrogen chloride (104 mg.) in tetrahydrofuran (1.0 ml.). Stirring is continued at room temperature for 3 hours, and the reaction mixture is poured into water (400 ml.). The resulting mixture is filtered and the residue is washed with Water, and dried to yield a crude product.

30 Crystallization from acetone gives 9a,11/3-dichloro-l7a, 21-dihydroxy-4-pregnene-3,20-dione 21- acetate.

A suspension of 9u,11B-dichloro-l7a,21-dihydroxy-4- pregnene-3,20-dione ZI-acetate (1.0 g.) in 0.27 N methanolic perchloric acid (70 ml.) is stirred at room temperature for 17 hours. The reaction mixture is then poured into water (200 ml.) and filtered. The residue is washed with water and dried, giving a crude product, which is crystallized from acetone to yield 9a,11B-dichloro-l70:,21-dihydroxy-4-pregnene-3,20-dione.

To a stirred, cooled (05 C.) solution of 17a,21-dihydroxy-4,9(11)-pregnadiene-3,20-dione 21-acetate (1.0 g.) and lithium chloride (4.0 g.) in glacial acetic acid (40 ml.) is added N bromoacetamide (395 mg.) followed immediately by an anhydrous solution of hydrogen chloride (104 mg.) in tetrahydrofuran (1.0 ml.). Stirring is continued at room temperature for 3 hours, and the reaction mixture is precipitated with water and filtered. The residue is washed with water, and dried to yield a crude product. Crystallization from acetone gives 96(- bromo-l1fl-chloro-17ot,2l-dihydroxy 4 pregnene-3,20- dione 21-acetate.

A suspension of Qa-bromo-l1fl-chloro-17a,21-dihydroxy-4-pregnene-3,20-dione 2l-acetate 1.0 g.) in 0.27 N methanolic perchloric acid (70 ml.) is stirred at room temperature for 17 hours. The reaction mixture is then precipitated with water and filtered. The residue is washed with water and dried, giving a crude product which is recrystallized from acetone to yield 9or-bromo- 11B-chloro-17u,21-dihydroxy-4-pregnene-3,20-dione.

To a solution of 100 mg. of 9a,llfi-dichloro-l7ot,2ldihydroxy-4-pregnene-3,2'O-dione compound in 2 ml. of pyridine is added one milliequivalent of acetic anhydride. The mixture is allowed to stand overnight at room temperature. A mixture of ice and water is then added. After standing for about 30 minutes, the product is extracted with ethyl acetate. The ethyl acetate extract is washed successively with water, ice-cold 1 N sulfuric acid (until the pH of the aqueous layer is 1-3), saturated aqueous sodium bicarbonate (until the pH of the aqueous layer is 8), and water (until the aqueous layer is neutral). The ethyl acetate solution is dried with anhydrous sodium sulfate. The solvent is then distilled at about 40 C. in vacuo to afford the 9a,11,8-dichloro-17a,21-dihydroxy-4- pregnene-3,20-dione 2l-acetate which is isolated by the addition of Water and filtration.

A suspension containing 300 mg. of 9a,11fl-dichlorol7a,21-dihydroxy 4 pregnene 3,20 dione 21-acetate, 700 mg. of chloranil, 8.3 ml. of ethyl acetate and 1.7 ml. of acetic acid is refluxed for 17 hours under nitrogen. The reaction mixture is diluted with 40 ml. of ethyl acetate and filtered. The filtrate is washed sequentially with two 20 ml. portions of ice cold 10% aqueous sodium bisulfite solution, three 20 ml. portions of ice cold 5% aqueous potassium hydroxide solution and finally washed to neutrality with several 20 ml. portions of ice water. The aqueous washes are re-extracted with 50 ml. of ethyl acetate and treated as above. The combined organic phase is dried over sodium sulfate and concentrated in vacuo. The crude material dissolved in benzene is chromatographed on 15 g. of acid washed alumina. Elution with chloroforrmether 2:8 affords 90c, 11,6-dichloro-17a,2l-dihydroxy 4,6 pregnadiene-3,20- dione 21-acetate. This product is then hydrolyzed by treatment with a solution of potassium bicarbonate in aqueous methanol to form 9a,11fl-dichloro-17a,21-dihydroxy-4,6-pregnadiene-3,20-dione.

Example 6 A 5 g. sample of 90t-fl1lOI'O-1lB,170t,2l-trlhydIOXy-160tmethyl-4,6-pregnadiene-3,ZO-dione is dissolved in a mixture of 235 ml. of chloroform and ml. of methylene chloride, cooled in an ice bath with stirring and treated with 85 ml. of formaldehyde (37%). An equal volume (85 ml.) of cold concentrated hydrochloric acid is added from a funnel over a -minute interval with stirring and cooling. Th mixture is stirred at room temperature for four hours. The layers are separated and the organic layer is washed free of acid by washing three times with water and then with a 5% solution of sodium bicar bonate. The organic layers are washed free of bicarbonate, dried over magnesium sulfate and taken to dryness. The gummy residue is treated with enough hot methanol on a steam bath to effect trituration, and the resulting crystalline solid is separated by filtering the mixture while hot. (The filtrate is set aside and may deposit additional product overnight.) The crude product is dried to constant weight and purified by chromatography. The product is partially dissolved in 250 ml. of hot chloroform and diluted with an equal vol ume of hot benzene to complete solution. After cooling, the mixture is adsorbed in 100 g. of basic alumina and eluted with benzene and chloroform to give 17a, 20,20,2l-bis(methylenedioxy) 9oz fluoro 16cc methyl- 1lfl-hydroxy-4,6-pregnadiene-3-one.

The l7o,20,20,2l-bis(methylenedioxy) 90c fluoro- 16a-methyl llfl hydroxy-4,6-pregnadiene-3-one (3.25 g.) is dissolved in 76 ml. of dry pyridine and added to a cold solution prepared by the cautious addition of 3.25 g. of chromium trioxide (in portions) to 34.7 ml. of cold pyridine. The mixture is allowed to stand at room temperature overnight. The mixture is poured into water and extracted three times with ethyl acetate, avoiding excessive shaking especially during the third extraction. The combined ethyl acetate extracts are washed three times with 1 N sulfuric acid and then with water until neutral. The combined ethyl acetate extracts are dried over magnesium sulfate and taken to dryness to give 294 g. of product. The product is dissolved in benzene, adsorbed on basic alumina and eluted with 8:2 benzene:chloroform to give 17u,20,20,2l-bis(methylenedioxy)-9or-fiuoro-l6a-methyl 4,6 .pregnadiene-3,1ldione.

A 2.60 g. sample of 17a,20,20,21-bis(methylenedioxy)- 9a-fluoro-16a-methyl-4,6-pregnadiene-3,1l-dione is dissolved in 95 ml. of dry benzene using dry equipment and treated with 2.43 ml. of freshly distilled ethyl formate. About 1.19 g. of a dispersion of sodium hydride in mineral oil (about 51%) is added, followed by about 1.19 g. of freshly prepared dry sodium methoxide (dried at about 175 C. oil pump for 4 hours). The air in the system is again replaced with nitrogen and the mixture, which turns yellow at once, is stirred at room temperature for one and one-half hours. At this point the color of the reaction mixture is a dark orange. The mixture is chilled in an ice bath and a cold, saturated solution of sodium dihydrogen phosphate is added generally to decompose excess sodium hydride and neutralize the so dium methoxide. Ether is added and the layers are separated. The aqueous layers are back-extracted with ether and the combined organic layers are washed free of acid with water and then extracted three to four times with a 5% aqueous solution of sodium bicarbonate. These extracts are set aside. The product is now extracted four to five times with a cold 2% aqueous solution of sodium hydroxide. (In order to avoid emulsification, the aqueous alkali is gently poured into the separatory funnel and the layers are separated without shaking the funnel. The last two extracts may be shaken with care.) The dark liquor is back-extracted two times with ether, :and finally acidified in the cold with saturated aqueous solution of sodium dihydrogen phosphate. The neutral ether-benzene fraction should be set aside and processed as described below. The product is extracted into ether, and the ether extracts are washed free of acid with a saturated solution of sodium chloride. After drying over magnesium sulfate, the ether solution is taken to dryness and the amorphous product is crystallized from methanol to give 17a,20,20,2l-bis(methylenedioxy)-9afiuoro-Z-hydroxy-methylene 16oz methyl 4,6 preg- 3.2; nadiene-3,1l-dione. This material is satisfactory for use in the next step.

A 1.00 g. aliquot of 17a,20,20,21-bis(methylenedioxy)- 9u-fluoro 2 hydroxymethylen 16a methyl-4,6- pregnadiene-3,11-dione is suspended in 44 ml. of absolute ethanol and treated with 0.38 ml. of hydrazine hydrate (99l00% The air in the system is replaced with nitrogen and the mixture is quickly brought to the reflux temperature. After refluxing for one hour the mixture is taken to dryness; the residual oil is treated with water and the resulting amorphous solid is removed by filtration, washed thoroughly with water and dried. The yield is about 900 mg. The crude product is dissolved in absolute ethanol and concentrated in vacuo until the solid separates. The solid is redissolved by heating, and then allowed to crystallize slowly to afford l7a,20,20,Zl-bis (methylenedioxy) 9a fiuoro 16a methyl-11-oxo-4,6- pregnadieno-[3 ,2-c] pyrazole.

A 455 mg. aliquot of 17a,20,20,2l-bis(methylenedioxy)-9a-fluoro-16a-methyl-1l-oxo 4,6 pregnadieno-[3, 2-cl-pyrazole is suspended in 75 ml. of a solution of sodium borohydride in isopropanol which is prepared by suspending an excess of sodium borohydride in isopropanol, stirring vigorously for about 15 minutes, and filtering to separate the excess of sodium borohydride. To the suspension is added an 0.816 ml. aliquot of a solution of 0.55 ml. of triethylamine in 1.45 ml. of isopropanol. The mixture is stirred, and enough methylene chloride (about 30 ml.) is added, with cooling, to make the system homogeneous. One drop of water (ca. ml.) is added and the mixture is stirred in a nitrogen atmosphere at room temperature over-night. Insolubles generally separate out in the course of the reaction. The mixture is then cooled, and the excess of sodium borohydride is decomposed by the addition of cold 2.5 N hydrochloric acid. The mixture (pH ca. 5) is taken to dryness in vacuo and the residue is Washed with water and dried to give 17 x,20,20,2l-bis(methylenedioxy)-9a fluoro 11,6 hydroxy-l6rx-methyl-4,6-pregnadieno- 3,2-c] -pyrazole.

To a solution of 100 mg. of 17a,20,20,21-bis(methylenedi0xy)-9a-fluoro-1lfl-hydroxy-lM-methyl 4,6 pregnadieno-[3,2-c]pyrazole in 2 ml. of pyridine is added 0.5 ml. of acetic anhydride. The mixture is allowed to stand overnight at room temperature. A mixture of ice and water is then added. After standing for about 30 minutes, the product is extracted with ethyl acetate. The ethyl acetate extract is washed successively with water, ice-cold 1 N sulfuric acid (until the pH of the aqueous layer is 13), saturated aqueous sodium bicarbonate (until the pH of the aqueous layer is 8), and water (until the aqueous layer is neutral). The ethyl acetate is then distilled at about 40 C. in vacuo to afford the Nacetyl-17u,20,20,21-bis(rnethylenedioxy) 9a fluorolIB-hydroxy-16a-methyl-4,6-pregnadieno-[3,2-c] pyrazole which is isolated by the addition of water and filtration.

In accordance with the above procedure, but using an equivalent quantity of another acylating agent in place of acetic anhydride, there is obtained the corresponding N-acyl derivative.

The N-acetyl-l7u-20,20,21 bis(methylenedioxy) 9afluoro-l1,8-hydroxy-16ot-methyl-4,6-pregnadiene [3,2-c]'- pyrazole (25 mg.) is heated on a steam bath with 5 cc. of a 60% aqueous solution of formic acid for about 30 minutes. The excess reagent is removed under reduced pressure using a water bath at about 50 C. as the source of heat. The residue is flushed with n-hexane. The residue is then dissolved in acetone and precipitated with n-hexane to give an amorphous solid which is a mixture of N-acetyl-9a-fluoro-l1B,l7a,21-trihydroxy-l6amethyl-20-oxo-4,6 pregnadieno [3,2-clpy'razole and N- acetyl-9a-fluoro-2l-formyloxy-l1,8,l7a dihydroxy cmethyl-20-oxo-4,6-pregnadieno [3,2 clpyrazole, which compounds are separated by chromatography.

A 500 mg. aliquot of this crude product is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexan'e. The residue is washed with water, filtered and dried to constant weight to give 9OL-flUOrO- l 1,8, l7tx-2l-trihydroxy-l6ot-methyl-20-oxo-4,6 pregnadieno 3,2-c] pyrazole.

To a solution of 100 mg. of N-acetyl-9wfluoro-lli3, 17tx,21-trihydroxy-16a-methyl-20-oxo 4,6 pregnadieno- [3,2-c1pyrazole in2 m1. of pyridine is added one milliequivalent of acetic anhydride. The mixture is allowed to stand overnight at room temperature. A mixture of ice and water is then added. After standing for about 30 minutes, the product is extracted with ethyl acetate. The ethyl acetate extract is washed successively with Water, ice-cold 1 N sulfuric acid (until the pH of the aqueous layer is 13 saturated aqueous sodium bicarbonate (until the pH of the aqueous layer is 8), and water (until the aqueous layer is neutral). The ethyl acetate solution is dried with anhydrous sodium sulfate. The solvent is then distilled at about 40 C. in vacuo. The N-acetyl-9u-fluoro-1 1B,17ot,21-trihydroxy-16u methyl-20-oxo-4,6-pregnadieno[3,2 c] pyrazole 21 acetate is then isolated by addition of water and filtration.

In accordance with the above procedure, but using an equivalent quantity of another acylating agent in place of acetic anhydride, there is obtained the corresponding N-acetyl-9a-fiuoro-11,8,17ot,21 trihydroxy 16cc methyl- 20-oxo-4,6-pregnadieno-[3,2-c]pyrazole 21-acylate.

In accordance with the above procedure, but starting with the 9tx-fiuoro-1 1,8,17a,2l-trihydroxy-l6a-methyl-20- oxo-4,6-pregnadieno-[3,2-c]pyrazole and using two milliequivalents of another acylating agent, there is obtained the corresponding N-acyl-2l-acylate thereof.

Asolution of 5.73 g. of N-acyl-9a-fiuoro-l1fi,17a,21- trihydroxy-16a-methyl-20-oxo-4,6-pregnadieno [3,2 c]- pyrazole 21-acetate in 60 ml. of 80% (v./v.) acetic acid is refluxed for 1.5 hours. This solution is diluted with 400 ml. of ice-water and extracted with ethyl acetate. The ethyl acetate extract is washed with water and with saturated sodium bicarbonate solution, dried, and evaporated to dryness in vacuo. Recrystallization of the resulting product affords 9a-fluoro-11p,17u,21-trihydroxy-16amethyl-20-oxo-4,6-pregnadieno-[3,2-c]pyrazole 21 acetate.

To a solution of 85 mg. of N-acety1-9a-fluoro-11p,17ot,21- trihydroxy-16tx-methyl-20-oxo-4,6-pregnadieno [3,2 c]- pyrazole in 0.5 ml. of pyradine, cooled to C., is added 0.015 ml. of methane sulfonyl chloride. The resulting mixture is allowed to stand at a temperature of approximately 0 C. for a period of approximately 1 hour. Water is then added to the reaction mixture and the precipitate which forms is recovered by filtration, washed with water, and dried to give N-acetyl-9tx-fluoro-l1fl-17u, 21-trihydroxy-16a-methyl-20-oxo-4,6-pregnadieno-[3,2-c]- pyrazole 21-mesylate.

To. 180 mg. of N-acetyl-9a-fiuoro-11p,17u,2l-trihydroxy 16a methyl-20-oxo-4,6-pre-gna-dieno-[3,2-c]pyrazole 21-mesylate dissolved in ml. of acetone is added 300 mg. of sodium iodide. The resulting mixture is heated at reflux temperature 'for a period of approximately one hour, and the reaction solution is cooled to room temperature and diluted with water. The material which precipitates is recovered by filtration, washed with water, and dried to give N-acetyl-9ot-fluoro-11/3,17ot-dihydroxy- 21 iodo 16a. methyl-ZO-oxo-4,6 pregnadieno-[3,2-c]

pyrazole.

The N acetyl 9a-fluoro-l15,17a-dihydroxy-2l-iodo- 16a met-hyl- 20-oxo-4,6-pregnadieno-[3,2-c1pyrazole is dissolved in a mixture of 5 ml. of water and 5 ml. of ethanol. To the resulting suspension is added 500 mg. of sodium bisulfite, and the mixture is heated under reflux for a period of about 1 hr. The reaction solution is cooled, diluted with water, the material which separates is recovered by filtration. The product is washed with water, dried and recrystallized from ethyl acetate to give N acetyl 9a fluoro-l1B,17ot-dihydroxy-16a-methy1- 20-oxo-4,6-pregnadieno-[3,2-c]pyrazole.

A 500 mg. aliquot of the above product is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of 1.33 N solution of sodium vmethoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alkoxideis neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with water, filtered and dried to constant weight to give 9a-fluoro-llfi,l7a-dihydroxy 16a methyl 20-oxo-4,6 pregna-dien0-[3,2-c] pyrazole.

To a solution of 62 mg. of N-ZICCtYl-got-HUOI'O-l1B,170L,- 21 trihydroxy 160a methyl-20-oxo-4,6-pregnadieno- [3,2-c1pyrazole 21-mesylate in 1 ml. of freshly distilled anhydrous dimethyl-formamide is added enough anhydrous potassium fluoride to assure a saturated solution. The mixture is heated at 110 C. for 20 hours. Water is added to the cooled solution and the product is extracted into chloroform, dried over sodium sulfate and evaporated to dryness. The resulting product is a mixture of N acetyl-l7a,2l-epoxy-9a-lluoro-1lfl-hydroxy- 16a methyl-20-oxo-4,6-pregnadieno-[3,2-c]pyrazole and N acetyl 911,21 difiuoro 115,17a dihydroxy-16amethyl 20 oxo-4,6- pregnadieno-[3,2-clpyrazole which compounds are separated by partition chromatography, or by chromatography on silica gel.

A 500 mg. aliquot of the above product is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alkoxide is neutralized wit-h acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with water, filtered and dried to constant weight to give 9a,21-difluoro- 17a,2l dihydroxy 16a-methyl-20-oxo-4,6-pregnadieno- L3,2-c]pyrazole.

In accordance with the above procedures, but starting with the 9a,-fiuoro-l 113,17ot,2l-tri-hydroxy-l6-methylene- 4,6-pregnadiene-3,20adione in place of the 9a-flu0ro-1lfi; 17u,21 trihydroxy 16a methyl-4,6-pregnadiene-3,20- dione, there are obtained as products the corresponding iluoro 11 8,17a,21-trihydroxy-l6-methylene-11,2-0- dioxo-4,6-pregnadieno-[3,2-c]pyrazole and the N-acyl-, the 2l-acylate, and the N-acyl-Zl-acylate derivatives thereof in which the two acyl groups may be the same or different; the 90c fluoro-l7oc,2l-dihydroxy-l6-methylene- 1l,20-dioxo-4,6-pregnadieno-[3,2-c1pyrazole and the N- acyl derivative thereof, and the 9a,2l-difluoro-llfi,l7adihydroxy 16 methylene-11,20-dioxo-4,6-pre gnadieno- [3,2-c]pyrazole and the N-acyl derivates thereof.

A 500 mg. aliquot of the above product is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with water, filtered and dried to constant weight to give 90t-,21-dlfl1lO1'O'-170t,21- dihydroxy 16oz methyl 20 oxo 4,6 -pregnadieno- [3,2-c1-pyrazole.

Example 7 About 6 g. of 17a,20,20,21-bis(methylenedioxy)-1'l5- hydroxy-16a-methyl-4,6 pregnadiene-3-one (Example 4) is suspended in about 35 ml. of dry benzene, and to this suspension is added 6 ml. of ethyl formate and about 1 g. of freshly prepared sodium methoxi-de The mixture is allowed to stand at room temperature under nitrogen for 1% hours and is then cooled in an ice 'bath. The mixture is then acidified with an excess of a saturated aqueous solution of potassium dihydrogen phosphate. Ether is added and the product is extracted several times with a 2% aqueous solution of sodium hydroxide. The extracts are back-extracted with ether which is acidified with cold 2.5 N HCl, and then extracted with methylene chloride. The methylene chloride extracts are washed with aqueous saturated sodium chloride solution, dried over magnesium sulfate and then taken to dryness. The resulting product is crystallized with etherrpetroleum ether to give 17a,20,- 20,21 bis(methylenedioxy) llfi formyloxy 2 hydroxymethylene-l6a-methyl-4,6-pregnadiene-3-one.

To 1.422 g. of 17a,20,20,21-bis(met-hylenedioxy)-l113,- formyloxy 2 hydroxymethylene 16a methyl-4,6- pnegnadiene-3-one, suspended in 18 ml. of absolute ethanol, is added 0.45 ml. of phenylhydrazine. The reaction mixture is refluxed for 40 minutes under nitrogen and then cooled. The l7a,20,20',2l bis(methylenedioxy)- 116 formy-loxy 16ot-methyl-Z-p:he-nyl-4,6-pregnadieno- [3,2-c]pyrazole, which is formed as the major product, separates out and is recrystallized.

The l7a,20,20,21 bis(methylenedioxy) 11B forrnyloxy 16a methyl 2 phenyl-4,6-pregnadieno-[3,2-c] pyrazole (720 mg.) is heated in a steam bath with 24 ml. of a 60% aqueous solution of formic acid for about 30 minutes. The excess reagent is removed in vacuo using a water bath at about 50 C. as the source of heat. The residue is flushed four times with n-hexane and then dried at 60 C. in high vacuum to give a solid which is a mixture of llfi,l7a,2l-trihydroxy-16ot-methyl-20-oxo-2- 'p'henyl-4,6-pregnadieno-[3,2-c]pyrazole and ll/3,l7 x,2ltrihydroxy 160a methyl 20 oxo 2'- pheny-l 4,6- pregnadieno-[3,2-c]-pyrazo le 2l-forrnate.

A 500 mg. aliquot of this crude product is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with water, filtered and dried to constant weight to give llp,l7ix,2l trihydroxy 16a methyl-20-oxo-2-phenyl-4, G-pregnadieno- 3,2-c] pyrazole.

Example 8 To a solution of 0.5 millimole of l7a,20,20,2l-bis- (methylenedioxy 11B hydroxy 2 hydroxymethylenel6e-methyl-4,6-pregnadiene-3-one (Example 4) in about 3 ml. of absolute ethanol is added 0.6 millimole of sodium acetate and then 0.6 millimole of methylhydrazine sulfate. The mixture is refluxed under nitrogen for 40 minutes and then filtered hot. The filtrate is taken to dryness, water is added, and the l7a,20,20,2l-'bis(methylenedioxy)- N,16x dimethyl 11,8 hydroxy-4,6-pregnadieno-[3,2-c] pyrazole which is formed as the major component is removed by filtration.

Alternatcly, a mixture of 1,16a-dimethyl-, and 2',l6adimethyl 17a,20,20,21 bis(methylenedioxy) 11B hydroxy-4,6-pregnadieno-[3,2-c1pyrazole is prepared by heating 17a,20,20,2l-bis(methylenedioxy)-1lfihydroxy- 2 hydroxymethylene l6a-methyl-4,6-pregnadiene-3-one with methanol in the presence of p-toluenesulfonic acid to form the l7a,20,20,21-bis(methylenedioxy)-llB-hydroxy 2 methoxy-rnethylene-l6ot-methyl-4,6-pregnadiene-3-one, and then reacting the latter compound with methylhydrazine, following the detailed procedures given in Example 10, but using methylhydrazine instead of phenylhydrazine. The components of the mixture are separated by chromatography.

In accordance with all the above procedures, but using other alkyl substituted hydrazines such as ethyl-, phydroxyethyl-, propyl-, butylhydrazines, and the like, in place of methylhydr-azine, there are obtained the corresponding l-alkyland 2'-a1kyl-17a,20,20,21-bis(methylenedioxy) 11,8 hydroxy 16a methyl-4,6-pregn-adieno- [3,2-c]pyrazoles.

Alternatcly the l7a,20,20,2lbis(methylenedioxy)-N, 16a dimethyl 11B hydroxy 4,6 pregnadieno-[3,2-c] pyrazoles may be prepared by the following procedure:

The l7u,20,20,21-bis(methylenedioxy)-llfl-hydroxy-Z- hydroxymethylene 16oz methyl-4,6-pregnadiene-3-one is dissolved in 9.2 ml. of absolute ethanol and treated with a solution of 0.16 ml. of hydrazine hydrate dissolved in 0.16 ml. of absolute ethanol. The mixture is refluxed in a nitrogen atmosphere for about minutes and then evaporated to dryness under reduced pressure. The residue is washed three times with cold water and the resulting amorphous solid is dried at C. for one hour in high vacuum to give l7a,20,20,21-bis(methylenedioxy)- ll fl-hydroxyl 6ot-methyl-4,6-pregnadieno- 3,2-c] pyrazole.

A solution of about 0.47 millimole of l7a,20,20,21- bis(methylenedioxy) 11B hydroxy-16a-methyl-4,6-preg nadieno-[3,2-c]pyrazole in 10 ml. of benzene is treated with about 3038 mg. of about 51% sodium hydride (in oil suspension). After the addition of 2-3 ml. of dimethylforrnamide (dried over calcium hydride) and 5 ml. of methyl iodide, the mixture is stirred at room temperature overnight. The product is filtered, washed with methylene chloride, and the filtrate and washings are taken to dryness. The residue is treated with water and the product is filtered to afford as a major component the 17a,20,20,21-bis(methylenedioxy)-1lfl-hydroxy- N,16a-dimethyl-4,6-pregnadieno-[3,2-c1pyrazole.

In accordance with the above procedure, but using another alkylating agent, for example, ethyl iodide, propyl iodide and the like, in place of the methyl iodide, there is obtained the corresponding 2 N-alkyl-l7a,20,20,2lbis(methylenedioxy) 11,8 hydroxy-l6u-methyl-4,6-pregnadieno-[3,2-c]pyrazole.

The 17a,20,20,2l-'bis(methylenedioxy)-lIB-hydroxy-Z, l6a-dimethyl-4,6-pregnadieno-[3,2-c]pyrazole (15 mg.) is heated on a steam bath with 1 mlQof 60% formic acid for about 20 minutes and then filtered hot. The filtrate is taken to dryness, water is added, and a mixture of the l1/3,l7a,2l-trihydroxy-2,l6nt-dimethyl-20-oxo-4,6- pregnadieno-[3,2-c]pyrazole and its 2l-formate is re covered by filtration. A 500 mg. aliquot of this crude product is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodiumniethoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with water, filtered and dried to constant weight to give 11B,l7a,21-trihydroxy-2',l6u-dirnethyl-20-oxo-4,6-pregnadieno-[3,2-c] pyrazole.

To a solution of mg. of 11B,17a,21-trihydroxy-2, 16a-dimethyl-20-oxo-4,6-pregnadieno [3,2-c]pyrazole in 2 ml. of pyridine is added one milliequivalent of acetic anhydride. The mixture is allowed to stand overnight at room temperature. A mixture of ice and water is then added. After standing for about 30 minutes, the product is extracted with ethyl acetate. The ethyl acetate extract is washed successively with water, ice-cold l N sulfuric acid (until the pH of the aqueous layer is 1-3), saturated aqueous sodium bicarbonate (until the pH of the aqueous layer is 8), and water (until the aqueous layer is neutral). The ethyl acetate solution is dried with anhydrous sodium sulfate. The solvent is then distilled atabout 40 C. in vacuo. The 11B,17a,21-trihydroxy-2, 16a dimethyl 20 oxo 4,6-pregnadieno-[3,2-c1pyrazole 2l-acetate is then isolated by addition of water and filtration.

In accordance with the above procedure, but using an equivalent quantity of another acylating agent in place of acetic anhydride, there is obtained the corresponding l1/8,l7a,21 trihydroxy 2',l6a-dirnethyl-20-oxo-4,6 pregnadieno-[3,2-c]pyrazole 21-acylate.

To a solution of 85 mg. of 11/3,17a,21-trihydroxy- 2,16a-dimethyI-ZO-oxo-4,6-pregnadieno 3,2-c]pyrazole in 0.5 ml. of pyridine, cooled to C., is added 0.015 ml. of methane sulfonyl chloride. The resulting mixture is allowed to stand at a temperature of approximately 0 C. for a period of approximately 1 hour. Water is then added to the reaction mixture and the precipitate which forms is recovered by filtration, washed with water, and dried to give l1fl,17a,'2l-trihydroxy-2',16a-dimethyl-20-oxo-4,6-pregnadieno [3,2-c]pyrazole 21-mesylate.

To 180 mg. of 113,17;l-trihydroxy-2,16a-dimethyl- 20-oxo-4,6-pregnadieno-[3,2-c]pyrazole 21-mesylate dissolved in ml. of acetone is added 300 mg. of sodium iodide. The resulting mixture is heated at reflux temperature for :a period of approximately 1 hour, and the reaction solution is cooled to room temperature and diluted with water. The material which precipitates is recovered by filtration, washed with water, and dried to give 115,17a dihydroxy-Zl-iodo-Z,16a-dimethyl-20-ox0- 4,6-pregnadieno- 3 ,2-c] pyrazole.

The 11fl,17a-dihydroxy-2l-iodo 2',l6oc dirnethyl-ZO- oxo-4,6-pregnadieno-[3,2-c]pyrazole is dissolved in a mixture of 5 ml. of water and 5 ml. of ethanol. To the resulting suspension is added 500 mg. of sodium bisulfite, and the mixture is heated under reflux for a period of about 1 hour. The reaction solution is cooled, diluted with water, and the material Which separates is recovered by filtration. The product is washed with water, dried and recrystallized from ethyl acetate to give 11fl,17a-dihydroxy 2,16a dimethyl-20-oxo-4, 6-pregnadieno- [3,2-c1pyrazole.

To a solution of 62 mg. of 11,B,17a,21-trihydroxy- 2,16a-dimethyl-20-oxo-4,6-pregnadieno [3,2-c]pyrazole 21-mesylate in 1 ml. of freshly distilled anhydrous dimethyl-formamide is added enough anhydrous potassium fluoride to assure a saturated solution. The mixture is heated at 110 C. for 20 hours. Water is added to the cooled solution and the product is extracted into chloroform, dried over sodium sulfate and evaporated to dryness. The resulting product is a mixture of 17,21- epoxy-1 1fl-hydroxy-2',16a-dimethyl-20-oxo 4,6 pregnadieno-[3,2-c]pyrazole and 21-fiuoro-11fl,l7o-dihydroxy- 2,16a-dimethyl-20-oxo-4,6-pregnadieno [3,2-c1pyrazole, which compounds are separated by partition chromatography, or by chromatography on silica gel.

-In accordance with the above procedures beginning with the 2'-methyl-17a,20,20,21-bis(methylenedioxy)-115- hydroxy-4,6-pregnadieno-[3,2-c]pyrazole, but using the 1'-methyl-derivative in place of the 2'-methyl-derivative, there are obtained the corresponding 1'-methylcompounds.

In accordance with all of the above procedures, but starting with the 17u,20,20,2l-bis(methylenedioxy)-2- hydroxymethylene 4,6 pregnadiene-derivative which is obtained from each of the starting materials which are listed in columns 24, there are obtained the corresponding 1-methyl-and 2-methyl derivative.

Example 9 To 200 mg. of 17a,20,20,'21-bis(methylenedioxy)-l1 8- hydroxy-2-hydroxymethylene-16u-methyl 4,6 pregnadiene-3-one (Example 4) in 7 cc. of absolute ethanol is added 82 mg. of sodium acetate and then 102 g. of cyclohexylhydrazine oxalate. The mixture is refluxed under nitrogen for one hour. The insolubles are removed by filtration. The filtrate is taken to dryness. The residue is dissolved in 3 cc. of ether and the ether solution is washed successively with 2% aqueous sodium hydroxide and then with water to neutrality. The ether solution is then dried over magnesium sulfate, filtered and taken to dryness to give a residue which has as the major component the N-cyclohexyl 17u,20',20,21 his- (methylenedioxy) 1lit-hydroxy-16a-methyl-4,6-pregnadieno-[3,2-c]pyrazole.

Alternately, a mixture of l-cyclohexyl-and the 2'- cyclohexyl l7tx,20,20,2l bis(methylenedioxy) 11/3- hydroxy-4,6-pregnadieno-[3,2-c1pyrazole is prepared by heating 17u,-20,20,2l-bis(methylenedioxy)-lIii-hydroxy- Z-hydroxymethylene 16cc methyl-4,6-pregnadiene-3-one with methanol in the presence of p-toluenesulfonic acid to form the 17a,20,20,21-bis(methylenedioxy 11 3 hydroxy 2 methoxymethylene 16cc methyl-4,6-pregnadiene-3-one, and then reacting the latter compound with cyclohexylhydrazine following the detailed procedures given in Example 10, but using cyclohexylhydrazine instead of phenylhydrazine. The components of the mixture are separated by chromatography.

A mg. aliquot of the N-cyclohexyl-17a,-20,20,21- bis(methylenedioxy) 11,8-hydroxy-16a-methyl-4,6-pregnadieno-[3,2-c]pyrazole is heated under nitrogen with 5 cc. of a 60% aqueous solution of formic acid for about 40 minutes. The mixture is taken to dryness and water is then added. The product is extracted with chloroform, and the chloroform solution is washed with saturated aqueous sodium chloride solution, 5% aqueous sodium bicarbonate solution and then with water. The chloroform solution is dried over magnesium sulfate and then taken to dryness to give a residue. This is taken up in ether containing a little methanol, stirred with 75 mg. of Darco G-60 (a .decolorizing charcoal), filtered and taken to dryness to give N-cyclohexyl-liii-1704,21- trihydroxy-16a-methyl-20-oxo 4,6 pregnadieno-[3,2-c] pyrazole.

The 2'-cyclohexyl-11;8,17a,2l-trihydroxy-16a methyl- 20-oxo-4,6-pregnadieno-[3,2-c]pyrazole is converted into the '21-acetate, the 2-cyclohexyl-l1/8,l7adihydroxy-16umethyl-20-oxo-4,6-pregnadieno-[3,2-c] pyrazole, and into the 2 cyclohexyl 21 fluoro-l1B,17u-dihydroxy-16otmethyl-20-oxo-4,6-pregnadieno [3,2-c]pyrazole, following the detailed procedures given in Example 8 for the corresponding 2-metl1yl-derivatives.

In accordance with the above procedures beginning with the 2-cyclohexyl-17a,20,20,21-bis(methylenedioxy) 11/3 hydroxy 16a methyl 4,6 pregnadieno [3,2-c] pyrazole, but using the 1-cyclohexyl-de rivative in place of the 2'-cyclohexyl-derivative, there are obtained the corresponding 1-cyclohexyl-compounds.

In accordance with all of the above procedures, but starting with the l7a,20,20,2l-bis(methylenedioxy)-2- hydroxymethylene-4,6-pregnadiene derivative which is obtained from each of the starting materials which are listed in columns 2-4, there are obtained the corresponding 1'-cyclohexyl-and 2-cyclohexyl-derivatives.

In accordance with the above procedures, but using other cycloalkylhydrazines in place of cyclohexylhydrazine there are obtained the corresponding 1'-and 2-cycloalkyl derivatives.

Example 10 To a suspension of 25.0 g. of 11/3,17a,2l-trihydroxy- 6,16ot-dimethyl-4,6-pregnadiene-3,20-dione in 1.5 l. of alcohol-free chloroform cooled to about 5 C. in an ice bath is added with constant stirring 750 ml. of cold, concentrated hydrochloric acid and then 750 ml. of formalin (low in methanol). The mixture is removed from the ice bath and stirred at room temperature for 7 hours. The layers are separated and the aqueous phase is back-extracted twice with chloroform. The combined organic layers are washed twice with a 5% solution of sodium bicarbonate, and twice With a saturated salt solution. The solution is dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue is triturated with methanol to afford a crystalline solid. This material contains no detectable amount of starting material by paperstrip chromatography but shows two U.V. absorbing spots near the solvent front(methanol-formamide 2:1 vs. benzene-n-hexane 1:1). A 2.425 aliquot is recrystallized three times from a mixture of benzene 39 and n-hexane to give 17a,20,20,21-bis( methylenedioxy)- 1 1fi-hydroxy-6,16a-dimethyl-4,6-pregnadiene-3-one which is used in the subsequent step of the synthesis without further purification.

17a,20,20,21 bis(methylenedioxy)-11B-hydroxy-6,l6adimethyl-4,6-pregnadiene-3-one (500 mg.) is dissolved in 25 cc. of benzene and then about cc. of benzene is removed by distillation at normal pressure. The resulting solution is cooled to room temperature. Then 0.75 cc. of freshly distilled ethyl formate is added. The air in the system is replaced with nitrogen and 150 mg. of sodium hydride (as a 57% dispersion in mineral oil) is added. The mixture is stirred under nitrogen at room temperature for three hours. Then cc. of a saturated aqueous solution sodium dihydrogen phosphate is added and the product is extracted into ether. The ether extracts are extracted with 2 N sodium hydroxide and the sodium hydroxide extracts are acidified with sodium dihydrogen phosphate and extracted again into ether. The ether extract is evaporated to dryness to give about 500 mg. of a crude product. From the ether solution there is obtained about 290 mg. of yellow crystals, M.P. 220236 C. which is 17a,20,20,21-bis(methylenedioxy)-11/3-formyloxy 2 hydroxy-methylene 6,16a-dimethyl-4,6-pregnadiene-3-one. The analytical sample is recrystallized from ethyl acetate and has a melting point of 249-255 C., 04 217, I.R. 5.81 1 and 8.37 1. From the mother liquor is obtained about 127 mg. of l7a,20,20,2l-bis(methylenedioxy)-l1fl hydroxy 2 hydroxymethylene-6,16adimethyl-4,6-pregnadiene-3-one. The analytical sample is recrystallized from ether and has a melting point of 200-204 C., a -197, I.R. 6.05-6.2/L, and 64 The l7u,20,20,2l bis(rnethylenedioxy 11B hydroxy-2-hydroxymethylene 6,160; dimethyl 4,6-pregnadiene-3-one (1.19 g.) is dissolved in cc. of ethanol. Three hundred mg. of phenyl hydrazine is added and the mixture is refluxed under nitrogen for one hour. About 25 cc. of water is added. The product is then extracted into 150 cc. of ether. The extracts are washed with 2 N HCl, with saturated sodium bicarbonate, water and saturated sodium chloride solution, and then dried over sodium sulfate and evaporated to dryness to give about 1.2 g. of crude product. On crystallization from ether there is obtained as a major component the 17cc, 20,20,21 bis(methylenedioxy) 11B hydroxy 6,16adimethyl-2'-pheneyl-4,6-pregnadieno-[3,2-c1pyrazole.

Alternately, a mixture of the 1-phenyland 2'-phenyl- 17a,20,20,2l-bis(methylenedioxy) llfi-hydroxy 6,160cdimethyl-4,6-pregnadieno-[3,2-c1pyrazole is prepared by the following route: 21-bisi(methylenedioxy) 113 hydroxy-2-hydroxymethylene-6,16a-dimethyl-4,6-pregnadiene-3-one, 200 ml. of methanol, and 200 mg. of p-toluenesulfonic acid is heated to reflux temperature and then allowed to stand at room temperature for one hour. The reaction mixture is then diluted with water and extracted with ethyl acetate. The ethyl acetate extract is washed two times with 2 N aqueous sodium hydroxide solution and then with water. The ethyl acetate extract is then dried and concentrated in vacuo. The 17a,20,20,21 bis( niethylenedioxy)-1lfl-hydroxy 2 methoxymethylene-6,16a-dimethyl-4,6-pregnadiene-3-one is obtained by direct crystallization or by chromatograpy on acid-washed alumina and elution with ether: chloroform mixtures.

A mixture of 500 mg. of 17a,20,20,21-bis(methylenedioxy) 11B hyd'roxy 2 methoxymethylene-6,16a-dimethyl-4,6-pregnadiene-3-one), 100 ml. of ethanol, and 1 ml. of phenylhydrazine is heated under nitrogen until dissolved, and then allowed to stand under nitrogeen at room temperature over night. Acetic acid (2 ml.) is added and the mixture is allowed to stand for another 4 hours. The reaction mixture is then diluted with ethyl acetate, washed two times with 2 N sulfuric acid, two times with 2.5 N sodium hydroxide, and then two times with water. The ethyl acetate extract is then dried, con- A mixture of 1 gram of l7oc,20,20,-

centrated, and chromatographed on acid-washed alumina. Elution with benzene affords a product which on recrystallization from a mixture of benzene and ethyl acetate atfords the 17a,20,20,2l-bis(methylenedioxy)-11{3-hydroxy- 6,1611 dimethyl 1 phenyl-4,6-pregnadien-[3,2-c]pyra zole. Further elution with a mixture of 1:1 ether: petroleum ether and crystallization from benzene, affords the 17a,20,20,21 bis(methylenedioxy)-1lfl-hydroxy 6,1604- dimethyl 2 phenyl-4,6 pregnadieno [3,2-c]pyrazole. l7a,Z0,20,2l bis(methylenedioxy) 11B-hydroxy-6,16adimethyl 2 phenyl 4,6-pregnadieno-[3,2-c]pyrazole (430 mg), is heated on a steam bath under nitrogen with 40 cc. of a 60% aqueous solution of formic acid for about 30 minutes. About 40 cc of water is added and the mixture is then extracted into 200 cc. of chloroform. The chloroform solution is washed with water, saturated sodium bicarbonate solution and water, then dried over sodium sulfate and evaporated under vacuum to give 430 mg. of crude product. This is dissolved in 60 cc. of absolute methanol, and 0.1 equivalent of sodium methoxide in methanol is added. The mixture is stirred under nitrogen at room temperature for 15 minutes. It is then acidified with acetic acid and the solvent is removed under vacuum at room temperature. About 20 cc. of water is added and the product is extracted into 150 cc. of ethyl acetate. The ethyl acetate solution is washed with saturated sodium bicarbonate and then with water. It is then dried over sodium sulfate and taken to dryness to give an amorphous solid.

The crude product obtained above is dried in high vacuum and then dissolved in 4 cc. of pyridine. About 3 cc of acetic anhydride is added. The mixture is then heated on the steam bath for about 15 minutes and then evaporated to dryness in vacuo. About 20 cc. of water is added. The product is then extracted into 150 cc. of ethyl acetate, washed with saturated sodium bicarbonate solution and water, and dried over sodium sulfate. The solvent is removed in vacuo to give a residue which is crystallized from ethyl acetate-benzene to yield about 250 mg. of 11fi,17ot,21-trihydroxy-6,16u-dimethyl-20-oxo-2'- phenyl-4,6-pregnadieno- [3 ,2-c] pyrazole 21-acetate.

One hundred mg. of 11fi,17a,21-trihydroxy-6,16tx-dimethyl-20-oxo-2-4,6-pregnadieno-[3,2-c1pyrazole 21-acctate is dissolved in 10 cc. of absolute methanol, and 1.1 equivalents of sodium methoxide in methanol is added. The mixture is stirred at room temperature under nitrogen for 15 minutes. The product is acidified with acetic acid and then evaporated at room temperature under vacuum. The residue is then taken up in cc. of chloroform, washed with water, saturated sodium bicarbonate solution, and water, and dried over sodium sulfate and evaporated to dryness to afford about 100 mg. of 113,170,- 2l-trihydroxy-6,16a dimethyl 20 oxo 2-phenyl-4,6- pregnadieno-[3,2-c1pyrazole.

The crude 11,6,17a,21 trihydroxy -6,16u-dimethyl-20 oxo 2 phenyl 4,6-pregnadieno-[3,2-c]pyrazole is dissolved in 1.2 cc. of dimethylformamide. The solution is cooled to 0 C. and 0.07 cc. of methane sulfonyl chloride is added. The mixture is kept at 0 C. for about one hour, 3 cc. of water is added and the product is extracted into 100 cc. of chloroform, washed with water, dried over sodium sulfate and taken to dryness to afford the crude 115,17rx,21 trihydroxy 6,16a-dimethyl-20-oxo-2- phenyl-4,6-pregnadieno-[3,2-c] pyrazole 21-mesylate.

The 11,8,17u,21 trihydroxy 6,16u-dimethyl-20-oxo- 2-phenyl-4,6=pregnadieno-[3,2-c]pyrazole 21-mesylate is suspended in 5.5 cc. of acetone and 117 mg. of sodium iodide is added. The mixture is refluxed under nitrogen for about one hour. It is then cooled on ice. On the addition of water there is formed a white precipitate which is filtered off, washed with water, and dried under vacuum to give the 11fl,17a dihydroxy 21 iodo 6,160:- dimethyl 20 oxo-2'-phenyl-4,6-pregnadieno-[3,2-c]pyrazole.

The above material is dissolved in 5 cc. of ethanol. 

